Pyrazolopyridazine derivatives

ABSTRACT

Fused pyradazine derivatives which are usefule as CDK inhibitors are described herein. The described invention alos includes methods of making such fused pyradazine derivatives as wells as methods of using the same in the treatment of hyperproliferative diseases.

This application is filed pursuant to 35 U.S.C. § 371 as a U.S. NationalPhase Application of International Application No. PCT/US02/39672 filedDec. 11, 2002, which claims priority from U.S. 60/341,798 filed Dec. 17,2001.

BACKGROUND OF THE INVENTION

The present invention relates to fused pyridazine derivatives, methodsfor the preparation of such fused pyridazines, and use of such fusedpyridazines in the treatment of certain diseases or conditions. Inparticular, the present invention relates to fused pyridazinederivatives useful as cyclin dependent kinase inhibitors and use of thefused pyridazines in the treatment of disorders mediated byinappropriate cyclin dependent kinase activity.

Effective chemotherapy, as well as radiotherapy, for cancer treatment,which has acceptable toxicity to normal cells, is a continuing goal inthe oncology field. Numerous cytotoxic agents are used in the treatmentof cancer, including cytotoxic agents that adversely affect rapidlydividing cells, including normal cells, that are in the process of celldivision. Typically, such agents may have effect on the cell cycle atG₁—the period between mitosis and DNA synthesis; S—the period of DNAsynthesis; G₂—the pre-mitotic interval; and/or M—the period of mitosisand are termed phase specific agents. Such agents are not effective inG_(o), the quiescent or resting cell phase. Therefore, suchanti-neoplastic agents are active against cells in the process of celldivision and are most effective against cancers that have a large growthfraction, that is, tumors that have a high percentage of dividing cells.Problematically, however, such agents also have an adverse effect onrapidly proliferating, normal tissues such as hair follicles andintestinal epithelium (See Goodman Et Gilman's, The Pharmacologic BasisOf Therapeutics 9^(th) Ed., pages 1230-1232.) which may lead tochemotherapy-induced alopecia (CIA) or mucositis. CIA as well asmucositis are frequent emotionally and/or physically distressing sideeffects of cancer chemo- and radiotherapies.

Protein kinases catalyze the phosphorylation of various residues inproteins including proteins involved in the regulation of cell growthand differentiation. Protein kinases play a critical role in the controlof cell growth and differentiation and are key mediators of cellularsignals leading to the production of growth factors and cytokines. See,for example, Schlessinger and Ullrich, Neuron 1992, 9, 383. The signalsmediated by protein kinases have also been shown to control growth,death and differentiation in the cell by regulating the processes of thecell cycle.

Progression through the eukaryotic cell cycle is controlled by a familyof protein kinases called cyclin dependent kinases (CDKs) and theirinteraction with a family of proteins termed cyclins (Myerson, et al.,EMBO Journal 1992, 11, 2909-17). The coordinate activation andinactivation of different cyclin/CDK complexes is necessary for normalprogression through the cell cycle (Pines, Trends in BiochemicalSciences 1993, 18, 195-7; Sherr, Cell 1993, 73, 1059-1065.). Both thecritical G1-S and G2-M transitions are controlled by the activation ofdifferent cyclin/CDK activities. In G1, both cyclin D/CDK4 and cyclinE/CDK2 are thought to mediate the onset of S-phase. Progression throughS-phase requires the activity of cyclin A/CDK2 whereas the activation ofcyclin A/cdc2 (CDK1) and cyclin B/cdc2 are required for the onset ofmetaphase. It is not surprising, therefore, that the loss of control ofCDK regulation is a frequent event in hyperproliferative diseases andcancer. (Pines, Current Opinion in Cell Biology 1992, 4, 144-8; Lees,Current Opinion in Cell Biology 1995, 7, 773-80; Hunter and Pines, Cell1994, 79, 573-82).

Consequently, inhibition of CDKs may prevent progression in the cellcycle in normal cells and limit the toxicity of cytotoxics which act inS-phase, G2 or mitosis. Such disruption of the cell cycle of normalproliferating cells should therefore protect proliferating cells such ashair follicles and epithelial mucosa from the effects of cytotoxicagents and thereby provide a potent treatment for side effectsassociated with cancer chemo- and radiotherapies.

The present inventors have discovered novel fused pyridazinederivatives, which are inhibitors of CDK, specifically CDK2 and CDK4activity. Such pyridazine derivatives are useful in the treatment of CIAand mucositis as well as cancer.

BRIEF SUMMARY OF THE INVENTION

In one aspect of the present invention, there is provided a compound ofFormula (I):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   wherein:-   D is N or CH-   R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃    alkoxy, halogen, —CF₃, hydroxy, cyano, —S(O)_(y)C₁-C₃ alkyl, or    —NR⁴R⁵;-   y is 0, 1, or 2;-   a is 1 or 2;-   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl,    heteroaryl, cyano, azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″,    —OS(O)₂R⁹, —S(O)_(y)R¹⁰, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁴R⁵,    —N(H)R′C(═NR⁴) NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵,    —OC(O)R⁷, or —N(R⁸)C(O)R⁸;-   R³ is -(Q)_(p)-(Q¹)    -   where        -   Q¹ is O, N(R⁸) or S(O)_(y), p is 0 or 1, y is 0, 1, or 2 and        -   Q¹ is C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl,            aryl substituted with —C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵,            heteroaryl, aralkyl, or —R⁶NR⁴R⁵;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and-   R⁵, together with the nitrogen atom to which they are bound, form a    heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃₋₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰,    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵,    —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸;-   R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)₂R⁹;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,    —C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,    —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸;-   R′ is C₁-C₃ alkylene; and-   R″ is —OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.

In a second aspect of the present invention, there is provided acompound of Formula (II):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   wherein:-   D is N or CH;-   R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃    alkoxy, —CF₃, halogen, hydroxy, cyano, —S(O)_(y)C₁-C₃ alkyl, or    —NR⁴R⁵;-   y is 0, 1, or 2;-   a is 1 or 2;-   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl,    heteroaryl, cyano, azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″,    —OS(O)₂R⁹, —S(O)_(y)R¹⁰, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁴R⁵,    —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵,    —OC(O)R⁷; or —N(R⁷)C(O)R⁷;-   Q¹ is C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl, aryl    substituted with —C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵, heteroaryl,    aralkyl, or —R⁶NR⁴R⁵;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they    are bound, form a heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰,    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵,    —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁷)C(O)R⁷;-   R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)₂R⁹;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,    —C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,    —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸;-   R′ is C₁-C₃ alkylene; and-   R″ is —OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.

In a third aspect of the present invention, there is provided a compoundof Formula (III):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   wherein:-   R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃    alkoxy, —CF₃, halogen, hydroxy, cyano, —S(O)_(y)C₁-C₃ alkyl, or    —NR⁴R⁵;-   y is 0, 1, or 2;-   a is 1 or 2;-   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₁    haloalkyl, —CF₃, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl,    heteroaryl, cyano, azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″,    —OS(O)₂R⁹, —S(O)_(y)NR¹⁰, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁴R⁵,    —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵,    —OC(O)R⁷, or —N(R⁷)C(O)R⁷;-   Q¹ is C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl, aryl    substituted with —C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵, heteroaryl,    aralkyl, or —R⁶NR⁴R⁵;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they    are bound, form a heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰,    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵,    —OC(O)NR⁴R⁵, OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁷)C(O)R⁷;-   R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)₂R⁹;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,    —C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,    —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸;-   R′ is C₁-C₃ alkylene; and-   R″ is —OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.

In a fourth aspect of the present invention, there is provided acompound of Formula (IV):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   wherein:-   R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃    alkoxy, C₁-C₆ haloalkyl, halogen, hydroxy, cyano, —S(O)_(y)C₁-C₃    alkyl, or —NR⁴R⁵;-   y is 0, 1, or 2;-   a is 1 or 2;-   R² is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆    haloalkyl, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl,    heteroaryl, cyano, azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″,    —OS(O)₂R⁹, —S(O)_(y)R¹⁰, —C(O)R⁷, —C(O)OR⁷, —C(O)NR⁴R⁵,    —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵,    —OC(O)R⁷, or —N(R⁷)C(O)R⁷;-   b is 1, 2, or 3;-   R^(x) is independently selected from hydrogen, halogen, C₁-C₆ alkyl,    C₁-C₆ hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂,    —OH, —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵,    —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, —SO₂OH,-   or-   b is 2 and the two R^(x) groups together with the phenyl group to    which they are bound form a fused group selected from:

-   wherein R_(y) and R_(z) are independently selected from hydrogen and    halogen,

-   wherein R is selected from —CF3, halogen, or hydrogen;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they    are bound, form a heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰,    —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵,    —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁷)C(O)R⁷;-   R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or —S(O)₂R⁹;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵,    aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,    —C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,    —C(═NR⁴)NR⁴R, —NR⁴R⁵, or —N(R⁸)C(O)R⁸;-   R¹¹ is C₁-C₆ alkyl;-   R′ is C₁-C₃ alkylene; and-   R″ is —OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.

In a fifth aspect of the present invention, there is provided a compoundof Formula (IVa):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   b is 1, 2, or 3;-   y is 0, 1 or 2;-   R^(x) is independently selected from hydrogen, halogen, C₁-C₆ alkyl,    C₁-C₆ hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂,    —OH, —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵,    —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, —SO₂OH,-   or-   b is 2 and the two R^(x) groups together with the phenyl group to    which they are bound form a fused group selected from:

-   wherein R_(y) and R_(z) are independently selected from hydrogen and    halogen,

-   wherein R is selected from —CF3, halogen, or hydrogen;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they    are bound, form a heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is NH₂, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or    heterocyclyl; and-   R¹¹ is C₁-C₆ alkyl.

In a sixth aspect of the present invention, there is provided a compoundof Formula (IVa):

-   or a salt, solvate, or physiologically functional derivative    thereof:-   b is 1, 2, or 3;-   y is 0, 1, or 2;-   R^(x) is independently selected from hydrogen, halogen, C₁-C₆ alkyl,    C₁-C₆ hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂,    —OH, —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵,    —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, —SO₂OH;-   R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,    —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they    are bound, form a heterocyclyl;-   R⁶ is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene,    alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;-   R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl;-   R¹⁰ is NH₂, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or    heterocyclyl; and-   R¹¹ is C₁-C₆ alkyl.

In a seventh aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients.

In an eighth aspect of the present invention, there is provided a methodof treating a disorder in a mammal, said disorder being mediated byinappropriate CDK activity, including: administering to said mammal atherapeutically effective amount of a compound of formula (I) or a salt,solvate or a physiologically functional derivative thereof.

In a ninth aspect of the present invention, there is provided a compoundof formula (I), or a salt, solvate, or a physiologically functionalderivative thereof for use in therapy.

In a tenth aspect of the present invention, there is provided the use ofa compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof in the preparation of a medicament for usein the treatment of a disorder mediated by inappropriate CDK activity.

In an eleventh aspect of the present invention, there is provided apharmaceutical composition including a therapeutically effective amountof a compound of formula (I), or a salt, solvate, or a physiologicallyfunctional derivative thereof and one or more of pharmaceuticallyacceptable carriers, diluents and excipients for preventing or reducingthe severity of epithelial cytotoxicity in a subject receiving cytotoxictherapy.

In a twelfth aspect of the present invention, there is provided a amethod of preventing or reducing the severity of epithelial cytotoxicityin a patient receiving cytotoxic therapy, comprising administering tosaid patient a therapeutically effective amount of a compound of formula(I) or a salt, solvate, or physiologically functional derivativethereof.

In a thirteenth aspect of the present invention, there is provided amethod of treating cancer in a mammal, including administering to saidmammal a therapeutically effective amount of a compound of formula (I),or salt, solvate or physiologically functional derivative thereof.

In a fourteenth aspect of the present invention, there is provided amethod of treating cancer in a mammal, including administering to saidmammal therapeutically effective amounts of (i) a compound of formula(I), or salt, solvate or physiologically functional derivative thereofand (ii) at least one additional anti-cancer therapy.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder; The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “lower” refers to a group having between oneand six carbons.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbon having from one to twelve carbon atoms, optionallysubstituted with substituents selected from the group consisting oflower alkyl, lower haloalkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, carboxamide optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, nitro, or lower haloalkyl such as lowerperfluoroalkyl, multiple degrees of substitution being allowed.Examples-of “alkyl” as used herein include, but are not limited to,methyl, ethyl, propyl, n-butyl, n-pentyl, isobutyl, isopropyl, and thelike.

As used herein, the terms “C₁-C₃ alkyl” and “C₁-C₆ alkyl” refer to analkyl group, as defined above, which contains at least 1, and at most 3or 6, carbon atoms respectively. Examples of “C₁-C₃ alkyl” and “C₁-C₆alkyl” groups useful in the present invention include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl.

As used herein, the term “alkylene” refers to a straight or branchedchain divalent hydrocarbon radical having from one to ten carbon atoms,optionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, carboxamide optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen andlower haloalkyl such as lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkylene” as used hereininclude, but are not limited to, methylene, ethylene, n-propylene,n-butylene, and the like.

As used herein, the terms “C₁-C₃ alkylene” and “C₁-C₄ alkylene” refer toan alkylene group, as defined above, which contains at least 1, and atmost 3 or 4, carbon atoms respectively. Examples of “C₁-C₃ alkylene” and“C₁-C₄ alkylene” groups useful in the present invention include, but arenot limited to, methylene, ethylene, n-propylene, isopropylene, andn-butylene.

As used herein, the term “alkenyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon doublebond, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, carboxamide optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen andlower haloalkyl such as lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkenyl” as used hereininclude, ethenyl, propenyl, 1-butenyl, 2-butenyl, and isobutenyl.

As used herein, the terms “C₂-C₄ alkenyl” and “C₂-C₆ alkenyl” refers toan alkenyl group as defined above containing at least 2, and at most 4or 6, carbon atoms respectively. Examples of “C₂-C₄ alkenyl” and “C₂-C₆alkenyl” groups useful in the present invention include, but are notlimited to, ethenyl, propenyl, 1-butenyl, 2-butenyl, and isobutenyl.

As used herein, the term “alkenylene” refers to an straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon double bonds, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, carboxamide optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower haloalkyl such as lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkenylene”as used herein include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, butene-1,2-diyl, and the like.

As used herein, the term “C₂-C₃ alkenylene” refers to an alkenylenegroup as defined above containing at least 2, and at most 3, carbonatoms. Examples of “C₂-C₃ alkenylene” groups useful in the presentinvention include, but are not limited to, ethene-1,2-diyl,propene-1,3-diyl, and the like.

As used herein, the term “alkynyl” refers to a hydrocarbon radicalhaving from two to ten carbons and at least one carbon-carbon triplebond, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, aryl, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, carboxamide optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen andlower haloalkyl such as lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “alkynyl” as used herein,include but are not limited to acetylenyl, propynyl, 1-butynyl,2-butynyl, 1-pentynyl, and 1-hexynyl.

As used herein, the terms “C₂-C₄ alkynyl” and “C₂-C₆ alkynyl” refers toan alkynyl group as defined above containing at least 2, and at most 4or 6, carbon atoms respectively. Examples of “C₂-C₄ alkynyl” and “C₂-C₆alkynyl” groups useful in the present invention include, but are notlimited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, and1-hexynyl.

As used herein, the term “alkynylene” refers to a straight or branchedchain divalent hydrocarbon radical having from two to ten carbon atomsand one or more carbon-carbon triple bonds, optionally substituted withsubstituents selected from the group which includes lower alkyl, loweralkoxy, lower alkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl,oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy,carbamoyl optionally substituted by alkyl, carboxamide optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,nitro, cyano, halogen and lower haloalkyl such as lower perfluoroalkyl,multiple degrees of substitution being allowed. Examples of “alkynylene”as used herein include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the terms “C₂-C₆ alkynylene”, refers to an alkynylenegroup as defined above containing at least 2, and at most 6, carbonatoms. Examples of “C₂-C₆ alkynylene” groups useful in the presentinvention include, but are not limited to, ethyne-1,2-diyl,propyne-1,3-diyl, and the like.

As used herein, the term “halogen” or “halo” refers to fluoro (—F),chloro (—Cl), bromo (—Br), or iodo (—I).

As used herein, the term “C₁-C₆ haloalkyl” refers to a straight orbranched chain hydrocarbon containing at least 1, and at most 6, carbonatoms substituted with at least one halogen, halogen being as definedherein. Examples of branched or straight chained “C₁-C₆ haloalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substitutedindependently with one or more halogens, e.g., fluoro, chloro, bromo andiodo.

As used herein, the term “C₁-C₆ hydroxyalkyl” refers to a straight or,branched chain hydrocarbon containing at least 1, and at most 6, carbonatoms substituted with at least one hydroxy, hydroxy being as definedherein. Examples of branched or straight chained “C₁-C₆ hydroxyalkyl”groups useful in the present invention include, but are not limited to,methyl, ethyl, propyl, isopropyl, isobutyl and n-butyl substitutedindependently with one or more hydroxy groups.

As used herein, the term “cycloalkyl” refers to a non-aromatic cyclichydrocarbon ring having from three to twelve carbon atoms, whichoptionally includes a C₁-C₄ alkylene linker through which it may beattached. Exemplary “cycloalkyl” groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

As used herein, the term “C₃-C₇ cycloalkyl” refers to a cycloalkyl groupas defined above having from three to seven carbon atoms, which alsooptionally includes a C₁-C₄ alkylene linker through which it may beattached. Exemplary “C₃-C₇ cycloalkyl” groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

As used herein, the term “C₃-C₇ cycloalkylene” refers to a non-aromaticalicyclic divalent hydrocarbon radical having from three to seven carbonatoms, optionally substituted with substituents selected from the groupwhich includes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, carboxamide optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen,lower haloalkyl such as lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkylene” as used hereininclude, but are not limited to, cyclopropyl-1,1-diyl,cyclopropyl-1,2-diyl, cyclobutyl-1,2-diyl, cyclopentyl-1,3-diyl,cyclohexyl-1,4-diyl, cycloheptyl-1,4-diyl, or cyclooctyl-1,5-diyl, andthe like.

As used herein, the term “C₃-C₇ cycloalkenyl” refers to a non-aromaticcyclic hydrocarbon ring having from three to seven carbon atoms, and oneor more carbon—carbon double bonds, which optionally includes a C₁-C₄alkylene linker through which it may be attached. Exemplary “C₃-C₇cycloalkenyl” groups include, but are not limited to, cyclobutenyl,cyclopentenyl, cyclohexenyl and cycloheptenyl.

As used herein, the term “C₃-C₇ cycloalkenylene” refers to anon-aromatic alicyclic divalent hydrocarbon radical having from three toseven carbon atoms, and one or more carbon-carbon double bondsoptionally substituted with substituents selected from the group whichincludes lower alkyl, lower alkoxy, lower alkylsulfanyl, loweralkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy, mercapto, aminooptionally substituted by alkyl, carboxy, carbamoyl optionallysubstituted by alkyl, carboxamide optionally substituted by alkyl,aminosulfonyl optionally substituted by alkyl, nitro, cyano, halogen,lower haloalkyl such as lower perfluoroalkyl, multiple degrees ofsubstitution being allowed. Examples of “cycloalkenylene” as used hereininclude, but are not limited to, 4,5-cyclopentene-1,3-diyl,3,4-cyclohexene-1,1-diyl, and the like.

As used herein, the term “heterocyclic” or the term “heterocyclyl”refers to a three to twelve-membered heterocyclic, non-aromatic, ringbeing unsaturated or having one or more degrees of unsaturationcontaining one or more heteroatomic substitutions selected from S, SO,SO₂, O, or N, said ring being optionally substituted with substituentsselected from the group consisting of lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, carboxamide optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, nitro, cyano,halogen, or lower haloalkyl such as lower perfluoroalkyl, multipledegrees of substitution being allowed. Such a ring may be optionallyfused to one or more of another “heterocyclic” ring(s), cycloalkylring(s), or aryl ring(s). Examples of “heterocyclic” include, but arenot limited to, tetrahydrofuranyl, pyranyl, 1,4-dioxanyl, 1,3-dioxanyl,1,3-benzodioxol-5-yl, 2,3-dihydro-1,4-benzodioxin-6-yl, piperidinyl,pyrrolidinyl, piperizinyl, 4-methyl-1-piperizinyl, 2-pyrrolidinone,morpholinyl, 4-morpholinyl propyl, tetrahydrothiopyranyl,tetrahydrothiophenyl, and the like.

As used herein, the term “aryl” refers to an optionally substitutedbenzene ring or to an optionally substituted benzene ring system fusedto one or more optionally substituted benzene rings to form, forexample, anthracene, phenanthrene, or napthalene ring systems. Exemplaryoptional substituents include lower alkyl, lower alkoxy, lowerhaloalkoxy, lower alkylsulfanyl, lower alkylsulfenyl, loweralkylsulfonyl, arylsulfanyl, heterocyclylsulfonyl, sulfo, oxo, hydroxy,mercapto, amino optionally substituted by alkyl or acyl, carboxy,carbamoyl optionally substituted by alkyl, carboxamide optionallysubstituted by alkyl, aminosulfonyl optionally substituted by alkyl,acyl, aroyl, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy,alkoxycarbonyl, nitro, cyano, halogen, lower haloalkyl such as lowerperfluoroalkyl, heterocyclyl, heteroaryl, or aryl, multiple degrees ofsubstitution being allowed. Examples of “aryl” groups include, but arenot limited to, phenyl, 2-naphthyl, 1-naphthyl, biphenyl, as well assubstituted derivatives thereof.

As used herein, the term “arylene” refers to a benzene ring diradical orto a benzene ring system diradical fused to one or more optionallysubstituted benzene rings, optionally substituted with substituentsselected from the group which includes lower alkyl, lower alkoxy, loweralkylsulfanyl, lower alkylsulfenyl, lower alkylsulfonyl, oxo, hydroxy,mercapto, amino optionally substituted by alkyl, carboxy, carbamoyloptionally substituted by alkyl, carboxamide optionally substituted byalkyl, aminosulfonyl optionally substituted by alkyl, acyl, aroyl,heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro,cyano, halogen, lower haloalkyl such as lower perfluoroalkyl, heteroaryland aryl, multiple degrees of substitution being allowed. Examples of“arylene” include, but are not limited to, benzene-1,4-diyl,naphthalene-1,8-diyl, anthracene-1,4-diyl, and the like.

As used herein, the term “aralkyl” refers to an aryl or heteroarylgroup, as defined herein, attached through a lower alkylene linker,wherein lower alkylene is as defined herein. Examples of “aralkyl”include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl,3-isoxazolylmethyl, 5-methyl-3-isoxazolylmethyl, and 2-imidazoyly ethyl.

As used herein, the term “heteroaryl” refers to a monocyclic five toseven membered aromatic ring, or to a fused bicyclic aromatic ringsystem comprising two of such monocyclic five to seven membered aromaticrings. These heteroaryl rings contain one or more nitrogen, sulfur,and/or oxygen heteroatoms, where N-oxides and sulfur oxides and dioxidesare permissible heteroatom substitutions and may be optionallysubstituted with up to three members selected from a group consisting oflower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, carboxamide optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerhaloalkyl such as lower perfluoroalkyl, heteroaryl, or aryl, multipledegrees of substitution being allowed. Examples of “heteroaryl” groupsused herein include furanyl, thiophenyl, pyrrolyl, imidazolyl,pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, is oxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl,benzimidazolyl, benzoxazolyl, benzothiophenyl, indolyl, indazolyl, andsubstituted versions thereof.

As used herein, the term “heteroarylene” refers to a five to sevenmembered aromatic ring diradical, or to a polycyclic heterocyclicaromatic ring diradical, containing one or more nitrogen, oxygen, orsulfur heteroatoms, where N-oxides and sulfur monoxides and sulfurdioxides are permissible heteroaromatic substitutions, optionallysubstituted with substituents selected from the group consisting of:lower alkyl, lower alkoxy, lower alkylsulfanyl, lower alkylsulfenyl,lower alkylsulfonyl, oxo, hydroxy, mercapto, amino optionallysubstituted by alkyl, carboxy, carbamoyl optionally substituted byalkyl, carboxamide optionally substituted by alkyl, aminosulfonyloptionally substituted by alkyl, acyl, aroyl, heteroaroyl, acyloxy,aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halogen, lowerhaloalkyl such as lower perfluoroalkyl, heteroaryl, or aryl, multipledegrees of substitution being allowed. For polycyclic aromatic ringsystem diradicals, one or more of the rings may contain one or moreheteroatoms. Examples of “heteroarylene” used herein are furan-2,5-diyl,thiophen-2,4-diyl, 1,3,4-oxadiazol-2,5-diyl, 1,3,4-thiadiazol-2,5-diyl,1,3-thiazol-2,4-diyl, 1,3-thiazol-2,5-diyl, pyridin-2,4-diyl,pyridin-2,3-diyl, pyridin-2,5-diyl, pyrimidin-2,4-diyl,quinolin-2,3-diyl, and the like.

As used herein, the term “hydroxy” refers to the group —OH.

As used herein, the term “alkoxy” refers to the group R_(a)O—, whereR_(a) is alkyl as defined above and the terms “C₁-C₃ alkoxy” and “C₁-C₆alkoxy” refer to the group R_(a)O—, where R_(a) is C₁-C₃ alkyl or C₁-C₆alkyl respectively as defined above.

As used herein, the term “haloalkoxy” refers to the group R_(a)O—, whereR_(a) is haloalkyl as defined above and the terms “C₁-C₃ haloalkoxy” and“C₁-C₆ haloalkoxy” refer to the group R_(a)O—, where R_(a) is C₁-C₃haloalkyl or C₁-C₆ haloalkyl respectively as defined above.

As used herein the term “aralkoxy” refers to the group R_(b)R_(a)O—,where R_(a) is alkylene and R_(b) is aryl, both as defined above.

As used herein, the term “alkylsulfanyl” refers to the group R_(a)S—,where R_(a) is alkyl as defined above.

As used herein, the term “arylsulfanyl” refers to the group R_(a)S—,where R_(a) is aryl as defined above.

As used herein, the term “alkylsulfenyl” refers to the group R_(a)S(O)—,where R_(a) is alkyl as defined above.

As used herein, the term “alkylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a)is alkyl as defined above.

As used herein, the term “heterocyclylsulfonyl” refers to the groupR_(a)S(O)₂—, where R_(a) is heterocyclyl as defined above.

As used herein, the term “oxo” refers to the group ═O.

As used herein, the term “mercapto” refers to the group —SH.

As used herein, the term “carboxy” refers to the group —COOH.

As used herein, the term “cyano” refers to the group —CN.

As used herein the term “cyanoalkyl” refers to the group —R_(a)CNwherein R_(a) is C₁-C₃ alkylene as defined above. Exemplary “cyanoalkyl”groups useful in the present invention include, but are not limited to,cyanomethyl, cyanoethyl, and cyanopropyl.

As used herein the term “nitro” refers to the group —NO₂.

As used herein the term “azido” refers to the group —N₃.

As used herein, the term “aminosulfonyl” refers to the group —SO₂NH₂.

As used herein, the term “carbamoyl” refers to the group —OC(O)NHR_(a),where R_(a) is hydrogen or alkyl as defined herein.

As used herein, the term “carboxamide” refers to the group —C(O)NH₂.

As used herein, the term “sulfanyl” shall refer to the group —S—.

As used herein, the term “sulfenyl” shall refer to the group —S(O)—.

As used herein, the term “sulfonyl” shall refer to the group —S(O)₂— or—SO₂—.

As used herein, the term “sulfo” shall refer to the group —S(O)₂OH.

As used herein, the term “acyl” refers to the group R_(a)C(O)—, whereR_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyl” refers to the group R_(a)C(O)—, whereR_(a) is aryl as defined herein.

As used herein, the term “heteroaroyl” refers to the group R_(a)C(O)—,where R_(a) is heteroaryl as defined herein.

As used herein, the term “alkoxycarbonyl” refers to the groupR_(a)OC(O)—, where R_(a) is alkyl as defined herein.

As used herein, the term “acyloxy” refers to the group R_(a)C(O)O—,where R_(a) is alkyl, cycloalkyl, or heterocyclyl as defined herein.

As used herein, the term “aroyloxy” refers to the group R_(a)C(O)O—,where R_(a) is aryl as defined herein.

As used herein, the term “heteroaroyloxy” refers to the, groupR_(a)C(O)O—, where R_(a) is heteroaryl as defined herein.

As used herein, the term “optionally” means that the subsequentlydescribed event(s) may or may not occur, and includes both event(s),which occur, and events that do not occur.

As used herein, the term “physiologically functional derivative” refersto any pharmaceutically acceptable derivative of a compound of thepresent invention, for example, an ester or an amide, which uponadministration to a mammal is capable of providing (directly orindirectly) a compound of the present invention or an active metabolitethereof. Such derivatives are clear to those skilled in the art, withoutundue experimentation, and with reference to the teaching of Burger'sMedicinal Chemistry And Drug Discovery, 5^(th) Edition, Vol 1:Principles and Practice, which is incorporated herein by reference tothe extent that it teaches physiologically functional derivatives.

As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) (II), (III), (IV), or (IVa) or a salt or physiologicallyfunctional derivative thereof and a solvent. Such solvents for thepurpose of the invention may not interfere with the biological activityof the solute. Examples of suitable solvents include, but are notlimited to, water, methanol, ethanol and acetic acid. Preferably thesolvent used is a pharmaceutically acceptable solvent. Examples ofsuitable pharmaceutically acceptable solvents include water, ethanol andacetic acid. Most preferably the solvent used is water.

The compounds of formulae (I), (II), (III), (IV), or (IVa) have theability to, crystallize in more than one form, a characteristic, whichis known as polymorphism, and it is understood that such polymorphicforms (“polymorphs”) are within the scope of formulae (I), (II), (III),(IV), and (IVa). Polymorphism generally can occur as a response tochanges in temperature or pressure or both and can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

As used herein, the term “substituted” refers to substitution with thenamed substituent or substituents, multiple degrees of substitutionbeing allowed unless otherwise stated.

Certain of the compounds described herein may contain one or more chiralatoms, or may otherwise be capable of existing as two enantiomers.Accordingly, the compounds of this invention may include mixtures ofenantiomers as well as purified enantiomers or enantiomerically enrichedmixtures. Also included within the scope of the invention are theindividual isomers of the compounds represented by formula (I), (II),(III), (IV), and (IVa) above as well as any wholly or partiallyequilibrated mixtures thereof. The present invention also covers theindividual isomers of the compounds represented by the formulas above asmixtures with isomers thereof in which one or more chiral centers areinverted.

It is to be understood that the following embodiments refer to compoundswithin the scope of formula (I), formula (II), formula (III), formula(IV), and formula (IVa) as defined above unless specifically limited bythe definition of each formula or specifically limited otherwise. It isalso understood that the, embodiments of the present invention describedherein, including uses and compositions, while typically described interms of formula (I) are also applicable to compounds of formula (II),formula (III), formula (IV) and formula (IVa).

It is also understood that the recited “aryl”, “heteroaryl”, or“heterocycyl” groups may optionally be substituted as indicated above inthe definitions for “aryl”, “heteroaryl”, and “heterocyclyl”respectively. Furthermore, such “aryl”, “heteroaryl”, and “heterocyclyl”groups may be substituted as specifically indicated with additionalgroups other than those recited in said definitions.

In one embodiment, D is N. In another embodiment, D is CH.

In one embodiment, R¹ is hydrogen or C₁-C₆ alkyl. In a preferredembodiment, R¹ is hydrogen. In another embodiment, R¹ is C₁-C₆ alkyl,preferably methyl, ethyl, or n-butyl.

In one embodiment, R² is hydrogen, C₁-C₆ alkenyl, heterocyclyl, aryl,heteroaryl, —OR⁸, S(O)_(y)R¹⁰, and —NR⁴R⁵. In a preferred embodiment, R²is hydrogen, heterocyclyl, aryl, heteroaryl, or —OR⁸. In a morepreferred embodiment, R² is hydrogen. In another embodiment, R² is —OR⁸,wherein R⁸ is hydrogen, methyl and isopropyl.

In an alternative embodiment, R² is heterocyclyl, preferably morpholinylor pyrrolidinyl; aryl, preferably phenyl; or heteroaryl, preferablypyridinyl or thienyl.

In one embodiment, Q is N(R⁸), p is 1, and Q¹ is C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, or aryl. In a preferred embodiment, Q isN(R⁸), p is 1, and Q¹ is C₃-C₇ cycloalkyl. In a more preferredembodiment, Q is N(R⁸), p is 1, and Q¹ is cyclopropyl.

In another embodiment, Q is N(R⁸), p is 1, and Q¹ is aryl. In apreferred embodiment, Q is N(R⁸), p is 1, and Q¹ is phenyl or phenylsubstituted with at least one of C₁-C₆ alkyl, halogen, cyano, carboxy,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, nitro, heteroaryl, or heterocyclyl.

In one embodiment Q is S(O)_(y), p is 1, y is 0, and Q¹ is C₁-C₆ alkyl,preferably methyl. In another embodiment Q is 0, p is 1, and Q¹ is C₁-C₆alkyl, preferably isopropyl.

In one embodiment, the compound of formula (I) is a compound of Formula(II):

-   or a salt, solvate, or physiologically functional derivative    thereof.

In one embodiment, the compound of formula (I) is a compound of formula(III):

-   or a salt, solvate, or physiologically functional derivative    thereof.

In another embodiment, the compound of formula (I) is a compound offormula (IV):

-   or a salt, solvate, or physiologically functional derivative    thereof, wherein b is 1, 2, or 3 and R^(x) is hydrogen, halogen,    C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆    haloalkyl, —NO₂, —OH, —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵,    —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, or —SO₂OH; preferably, b    is 1 or 2 and R^(x) is halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl,    —CN, C₁-C₆ haloalkyl, —NO₂, heterocyclyl, or —NR⁴R⁵; more    preferably, b is 1 and R^(x) is —CH₃, —CH₂CH₃, —CF₃, —CN, or —NO₂;    alternatively b is 2 and the two R^(x) groups together with the    phenyl group to which they are bound form a fused group selected    from:

-   wherein R_(y) and R_(z) are independently selected from hydrogen and    halogen,

-   wherein R is selected from —CF₃, halogen, or hydrogen.

In another embodiment, the compound of formula (I) is a compound offormula (IVa):

-   or a salt, solvate, or physiologically functional derivative    thereof, wherein, b is 1, 2, or 3 and R^(x) is hydrogen, halogen,    C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆    haloalkyl, —NO₂, —OH, —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵,    —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, or —SO₂OH; preferably, b    is 1 or 2 and R^(x) is halogen, C₁-C₆ alkyl, C₁₋₆ hydroxyalkyl, —CN,    C₁-C₆ haloalkyl, —NO₂, heterocyclyl, or —NR⁴R⁵; more preferably, b    is 1 and R^(x) is —CH₃, —CH₂CH₃, —CF₃, —CN, or —NO₂; alternatively b    is 2 and the two R^(x) groups together with the phenyl group to    which they are bourid form a fused group selected from:

-   wherein R_(y) and R_(z) are independently selected from hydrogen and    halogen,

-   wherein R is selected from —CF₃, halogen, or hydrogen;

In another embodiment, the compound of formula (I) is a compound ofFormula (IVa):

-   or a salt, solvate, or physiologically functional derivative    thereof, wherein b is 1, 2, or 3; y is 0, 1, or 2; and R^(x) is    independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆    hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH,    —OR⁹, aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵,    —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, —SO₂OH; preferably b is 1 or 2 and    R^(x) is independently selected from hydrogen, halogen, C₁-C₆ alkyl,    —CN, —C(O)OH, —C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹; more preferably    preferably b is 1 or 2 and R^(x) is independently selected from    hydrogen, halogen, —CN, —C₁-C₆ haloalkyl, or —NO₂; most preferably    preferably b is 1 and R^(x) is selected from —F, —CH₃, —CN, —CF₃, or    —NO₂.

Specific examples of compounds of the present invention include thefollowing:

-   N-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-cyclopropyl-N-methyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   4-pyrazolo[1,5-b]pyridazin-3-yl-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine;-   N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(4-chlorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(4-fluorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   3-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile;-   4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzoic    acid;-   4-pyrazolo[1,5-b]pyridazin-3-yl-N-[3-(trifluoromethyl)phenyl]-2-pyrimidinamine;-   N-(3-nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(2-chlorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(4-methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   4-pyrazolo[1,5-b]pyridazin-3-yl-N-(3,4,5-trimethoxyphenyl)-2-pyrimidinamine;-   N-[3-(1,3-oxazol-5-yl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1H-benzimidazol-6-amine;-   N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-benzoxazol-2-amine;-   N-(6-chloro-1H-benzimidazol-2-yl)-N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amine;-   N-(+chlorobenzyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N¹,N¹-dimethyl-N³-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-propanediamine    methanesulfonate;-   N-[3-(4-morpholinyl)propyl]-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[3-(4-methyl-1-piperazinyl)propyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   1-{3-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]propyl}-2-pyrrolidinone;-   N-[3-chloro-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-S    pyrimidinamine;-   N-[4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[3-chloro-4-(4-morpholinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-{4-[(diethylamino)methyl]phenyl}-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[2-(diethylamino)ethyl]-4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzamide;-   N-cyclopropyl-4-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   N-cyclopropyl-4-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   4-(2-butylpyrazolo[1,5-b]pyridazin-3-yl)-N-cyclopropyl-2-pyrimidinamine;-   N-[4-(4-methyl-1-piperazinyl)phenyl]-4-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   4-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;-   4-(2-butylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;-   N-cyclopropyl-4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;-   3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-ol;-   N-cyclopropyl-4-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   N-[4-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinyl]-N-[4-(4-methyl-1-piperazinyl)phenyl]amine;-   3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yl    trifluoromethanesulfonate;-   4-[6-(2-chlorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-cyclopropyl-2-pyrimidinamine;-   N-cyclopropyl-4-[6-(2-thienyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;-   N-cyclopropyl-4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;-   N-cyclopropyl-4-(6-vinylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;-   N-cyclopropyl-4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;    N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-amine;-   N-cyclopropyl-4-[6-(1-pyrrolidinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;-   N-cyclopropyl-4-[6-(2-fluoro-4-pyridinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;-   N-cyclopropyl-4-[6-(phenylsulfanyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;-   4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-(4-methoxyphenyl)-2-pyrimidinamine;-   4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;-   N¹,N¹-dimethyl-N⁴-{4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}-1,4-benzenediamine;-   1-(dimethylamino)-3-[4-({4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}amino)phenoxy]-2-propanol;-   N-(1,3-benzodioxol-5-yl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-[3-methoxy-5-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile;-   N-(4-nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(3-methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(3,5-dimethylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;-   N-(4-aminosulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;    and-   N-(4-methylsulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;    or salts, solvates, and physiologically functional derivatives    thereof.

Additional examples of compounds of the present invention, which can beprepared according to the Schemes and Examples following are depicted inTable I:

TABLE 1 (IVc)

# A D E J 62 —CF₃ —H —H —H 63 —SO₂NH₂ —H —H —H 64 —H —H —CF₃ —H 65 —H —F—H —H 66 —H —CH₃ —H —H 67 —H —CH₃ —N(H)C(O)CH₃ —H 68 —H —CH₂CH3 —H —H 69—H —CH(CH₃)CH₃ —H —H 70 —H —C(CH₃)₃ —H —H 71 —H —C(O)OH —H —H 72 —H—CH(OH)CH₃ —H —H 73 —H —S(O)₂NH₂ —H —H 74 —H —S(O)₂CH₂CH₂OH —H —H 75 —H—S(O)₂OH —Cl —H 76 —H —OCF₃ —H —H 77 —H —OCF₂CF₂H —H —H 78 —H —N(CH₃)₂—H —H 79 —Cl —H —S(O)₂CH₃ —H 80 —F —NO₂ —H —H 81 —H —NO₂ —F —H 82 —H—NO₂ —OH —H 83 —H —NO₂ —C(O)OH —H 84 —H —NO₂ —S(O)₂OH —H 85 —H —NO₂ —CF₃—H 86 —H —NO₂ —H —OCH₃ 87 —H —NO₂ —H —C(O)OH 88 —H —NO₂ —H —H 89 —H —CN—CH₃ —H 90 —H —CN —Cl —H 91 —H —CN —F —H 92 —H —CN

—H 93 —H —CN

—H 94 —H —CN —OH —H 95 —H —CN —H —CF₃ 96 —H —CN

—H 97 —H —CF₃ —F —H 98 —H —CF₃ —NO₂ —H 99 —H —CF₃ —CN —H 100 —H —CF₃—OCH₃ —H 101 —H —CF₃ —CH₃ —H 102 —H —CF₃ —OH —H 103 —H —CF₃ —H —F 104 —H—CF₃ —H —C(O)OH 105 —H —CF₃ —H —NO₂ 106 —H —CF₃ —H —OH 107 —H —CF₃ —H—OC(O)CH₃ 108 —Cl —CF₃ —H —H 109 —CH₃ —CF₃ —H —H 110 —H —CF3

—H 111 —H —C(O)OH

—H 112 —H

—H

Typically, the salts of the present invention are pharmaceuticallyacceptable salts. Salts encompassed within the term “pharmaceuticallyacceptable salts” refer to non-toxic salts of the compounds of thisinvention. Salts of the compounds of the present invention may compriseacid addition salts derived from a nitrogen on a substituent in thecompound of formula (I). Representative salts include the followingsalts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, monopotassium maleate,mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, potassium, salicylate, sodium, stearate, subacetate,succinate, tannate, tartrate, teoclate, tosylate, triethiodide,trimethylammonium and valerate. Other salts, which are notpharmaceutically acceptable, may be useful in the preparation ofcompounds of this invention and these form a further aspect of theinvention.

While it is possible that, for use in therapy, therapeutically effectiveamounts of a compound of formula (I), as well as salts, solvates andphysiological functional derivatives thereof, may be administered as theraw chemical, it is possible to present the active ingredient as apharmaceutical composition. Accordingly, the invention further providespharmaceutical compositions, which include therapeutically effectiveamounts of compounds of the formula (I) and salts, solvates andphysiological functional derivatives thereof, and one or morepharmaceutically acceptable carriers, diluents, or excipients. Thecompounds of the formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are as described above. The carrier(s),diluent(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the formulation and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical formulation including admixing a compound of theformula (I), or salts, solvates and physiological functional derivativesthereof, with one or more pharmaceutically acceptable carriers, diluentsor excipients.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to700 mg, of a compound of the formula (I) depending on the conditionbeing treated, the route of administration and the age, weight andcondition of the patient. Preferred unit dosage formulations are thosecontaining a daily dose or sub-dose, as herein above recited, or anappropriate fraction thereof, of an active ingredient. Furthermore, suchpharmaceutical formulations may be prepared by any of the methods wellknown in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) route. Such formulations maybe prepared by any method known in the art of pharmacy, for example bybringing into association the active ingredient with the carrier(s) orexcipient(s).

Pharmaceutical formulations adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by comminuting thecompound to a suitable fine size and mixing with a similarly comminutedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavoring, preservative, dispersing and coloringagent can also be present.

Capsules are made by preparing a powder mixture as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants,disintegrating agents and coloring agents can also be incorporated intothe mixture. Suitable binders include starch, gelatin, natural sugarssuch as glucose or beta-lactose, corn sweeteners, natural and syntheticgums such as acacia, tragacanth or sodium alginate,carboxymethylcellulose, polyethylene glycol, waxes and the like.Lubricants used in these dosage forms include sodium oleate, sodiumstearate, magnesium stearate, sodium benzoate, sodium acetate, sodiumchloride and the like. Disintegrators include, without limitation,starch, methyl cellulose, agar, bentonite, xanthan gum and the like.Tablets are formulated, for example, by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally, with a binder such as carboxymethylcellulose, analiginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt ard/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder, such assyrup, starch paste, acadia mucilage or solutions of cellulosic orpolymeric materials, and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the result is imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Thecompounds of the present invention can also be combined with a freeflowing inert carrier and compressed into tablets directly without goingthrough the granulating or slugging steps. A clear or opaque protectivecoating consisting of a sealing coat of shellac, a coating of sugar orpolymeric material and a polish coating of wax can be provided.Dyestuffs can be added to these coatings to distinguish different unitdosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additives suchas peppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, can also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels.

Pharmaceutical formulations adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time. Forexample, the active ingredient may be delivered from the patch byiontophoresis as generally described in Pharmaceutical Research, 3(6),318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, he formulations are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical formulations adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical formulations adapted for rectal administration may bepresented as suppositories or as enemas.

Pharmaceutical formulations adapted for nasal administration wherein thecarrier is a solid include a coarse powder having a particle size forexample in the range 20 to 500 microns which is administered in themanner in which snuff is taken, i.e., by rapid inhalation through thenasal passage from a container of the powder held close up to the nose.Suitable formulations wherein the carrier is a liquid, foradministration as a nasal spray or as nasal drops, include aqueous oroil solutions of the active ingredient.

Pharmaceutical formulations adapted for administration by inhalationinclude fine particle dusts or mists, which may be generated by means ofvarious types of metered, dose pressurised aerosols, nebulizers orinsufflators.

Pharmaceutical formulations adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors including, for example,the age and weight of the animal, the precise condition requiringtreatment and its severity, the nature of the formulation, and the routeof administration, and will ultimately be at the discretion of theattendant physician or veterinarian. However, an effective amount of acompound of formula (I) for the treatment of neoplastic growth, forexample colon or breast carcinoma, will generally be in the range of 0.1to 100 mg/kg body weight of recipient (mammal) per day and more usuallyin the range of 1 to 10 mg/kg body weight per day. Thus, for a 70 kgadult mammal, the actual amount per day would usually be from 70 to 700mg and this amount may be given in a single dose per day or more usuallyin a number (such as two, three, four, five or six) of sub-doses per daysuch that the total daily dose is the same. An effective amount of asalt or solvate, or physiologically functional derivative thereof, maybe determined as a proportion of the effective amount of the compound offormula (I) per se. It is envisaged that similar dosages would beappropriate for treatment of the other conditions referred to above.

The compounds of the present invention and their salts and solvates, andphysiologically functional derivatives thereof, may be employed alone orin combination with other therapeutic agents for the treatment of theabove-mentioned conditions. In particular, in anti-cancer therapy,combination with other chemotherapeutic, hormonal or antibody agents isenvisaged as well as combination with surgical therapy and radiotherapy.Combination therapies according to the present invention thus comprisethe administration of at least one compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof, and the use of at leastone other cancer treatment method. Preferably, combination therapiesaccording to the present invention comprise the administration of atleast one compound of formula (I) or a pharmaceutically acceptable saltor solvate thereof, or a physiologically functional derivative thereof,and at least one other pharmaceutically active agent, preferably ananti-neoplastic agent. The compound(s) of formula (I) and the otherpharmaceutically active agent(s) may be administered together orseparately and, when administered separately this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

The compounds of the Formula (I) or salts, solvates, or physiologicallyfunctional derivatives thereof and at least one additional cancertreatment therapy may be employed in combination concomitantly orsequentially in any therapeutically appropriate combination with suchother anti-cancer therapies. In one embodiment, the other anti-cancertherapy is at least one additional chemotherapeutic therapy includingadministration of at least one anti-neoplastic agent. The administrationin combination of a compound of formula (I) or (II) or salts, solvates,or physiologically functional derivatives thereof with otheranti-neoplastic agents may be in combination in accordance with theinvention by administration concomitantly in (1) a unitarypharmaceutical composition including both compounds or (2) separatepharmaceutical compositions each including one of the compounds.Alternatively, the combination may be administered separately in asequential manner wherein one anti-neoplastic agent is administeredfirst and the other second or vice versa. Such sequential administrationmay be close in time or remote in time.

Anti-neoplastic agents may induce anti-neoplastic effects in acell-cycle specific manner, i.e., are phase specific and, act at aspecific phase of the cell cycle, or bind DNA and act in a noncell-cycle specific manner, i.e., are non-cell cycle specific andoperate by other mechanisms.

Anti-neoplastic agents useful in combination with the compounds andsalts, solvates or physiologically functional derivatives thereof offormula I include the following:

(1) cell cycle specific anti-neoplastic agents including, but notlimited to, diterpenoids such as paclitaxel and its analog docetaxel;vinca alkaloids such as vinblastine, vincristine, vindesine, andvinorelbine; epipodophyllotoxins such as etoposide and teniposide;fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine;antimetabolites such as allopurinol, fludurabine, methotrexate,cladrabine, cytarabine, mercaptopurine and thioguanine; andcamptothecins such as 9-amino camptothecin, topotecan, irinotecan,CPT-11 and the various optical forms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to,alkylating agents such as melphalan, chlorambucil, cyclophosphamide,mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine,and dacarbazine; anti-tumour antibiotics such as doxorubicin,daunomycin, epirubicin, idarubicin, mitomycin-C, dacttinomycin andmithramycin; and platinum coordination complexes such as cisplatin,carboplatin, and oxaliplatin; and

(3) other chemotherapeutic agents including, but not limited to,anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifeneand iodoxyfene; progestrogens such as megestrol acetate; aromataseinhibitors such as anastrozole, letrazole, vorazole, and exemestane;antiandrogens such as flutamide, nilutamide, bicalutamide, andcyproterone acetate; LHRH agonists and antagagonists such as goserelinacetate and luprolide, testosterone 5α-dihydroreductase inhibitors suchas finasteride; metalloproteinase inhibitors such as marimastat;antiprogestogens; urokinase plasminogen activator receptor functioninhibitors; cyclooxygenase type 2 (COX-2) inhibitors such as celecoxib;angiogenic inhibiting agents such as VEGFR inhibitors and TIE-2inhibitors; growth factor function inhibitors such as inhibitors of thefunctions of hepatocyte growth factor; erb-B2, erb-B4, epidermal growthfactor recentor (EGFr), platelet derived growth factor receptor (PDGFr),vascular endothelial growth factor receptor (VEGFR) and TIE-2; and othertyrosine kinase inhibitors such as cyclin dependent inhibitors such asCDK2 and CDK4 inhibitors other than those described in the presentinvention.

In another embodiment, therapeutically effective amounts of thecompounds of formula I or salts, solvates or physiologically derivedderivatives thereof and agents which inhibit growth factor receptorfunction may be administered in combination to a mammal for treatment ofa disorder mediated by inappropriate CDK activity, for instance in thetreatment of cancer. Such growth factor receptors include, for example,EGFr, PDGFr, erb-B2, VEGFr, or TIE-2. Growth factor receptors and agentsthat inhibit growth factor receptor function are described, forinstance, in Kath, John C., Exp. Opin. Ther. Patents (2000)10(6):803-818 and in Shawver et al DDT Vol 2, No. 2 February 1997.

In one aspect of the present invention, there is provided a method ofpreventing or reducing the severity of epithelial cytotoxicity in apatient receiving cytotoxic therapy, comprising administering to saidpatient a therapeutically effective amount of a compound of formula (I)or a salt, solvate, or physiologically functional derivative thereof.

In one aspect of the present invention, there is provided a method oftreating cancer in a mammal, including administering to said mammaltherapeutically effective amounts of (i) a compound of formula (I), orsalt, solvate or physiologically functional derivative thereof and (ii)at least one additional anti-cancer therapy. In one embodiment, theanti-cancer therapy is cytotoxic.

The compounds of formula (I) and salts, solvates and physiologicalfunctional derivatives thereof, are believed to have anticancer activityas a result of inhibition of the protein kinase CDK2 and/or CDK4 and itseffect on selected cell lines whose growth is dependent on CDK2 and/orCDK4 kinase activity.

The present invention thus also provides compounds of formula (I) andpharmaceutically acceptable salts or solvates thereof, orphysiologically functional derivatives thereof, for use in medicaltherapy, and particularly in the treatment of disorders mediated byinappropriate CDK activity.

The inappropriate CDK activity referred to herein is any CDK activity,that deviates from the normal CDK activity expected in a particularmammalian subject. Inappropriate CDK activity may take the form of, forinstance, an abnormal increase in activity; or an aberration in thetiming and or control of CDK activity. Such inappropriate activity mayresult then, for example, from overexpression or mutation of the proteinkinase or ligand leading to inappropriate or uncontrolled activation ofthe receptor. Furthermore, it is also understood that unwanted CDKactivity may reside in an abnormal source, such as a malignancy. Thatis, the level of CDK activity does not have to be abnormal to beconsidered inappropriate, rather the activity derives from an abnormalsource.

The present invention is directed to methods of regulating, modulating,or inhibiting CDK2 and/or CDK4 for the prevention and/or treatment ofdisorders related to unregulated CDK activity. In particular, thecompounds of the present invention can also be used in the treatment ofcertain forms of cancer. Furthermore, the compounds of the presentinvention can be used to provide additive or synergistic effects withcertain existing cancer chemotherapies and radiation, and/or be used toprovide protection from the epithelial cytotoxic effects of certainexisting cancer chemotherapies and radiation.

A further aspect of the invention provides a method of treatment of amammal suffering from a disorder mediated by inappropriate CDK activity,including susceptible malignancies, which includes administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable salt, solvate, or a physiologicallyfunctional derivative thereof. In a preferred embodiment, the disorderis cancer. In one embodiment the CDK is CDK2. In another embodiment, theCDK is CDK4. In another embodiment, the CDK is CDK2 and CDK4.

A further aspect of the invention provides a method of treatment of amammal suffering from cancer, which includes administering to saidsubject an effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof, or aphysiologically functional derivative thereof.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of a disordercharacterized by inappropriate CDK activity. In a preferred embodiment,the disorder is cancer. In one embodiment the CDK is CDK2. In anotherembodiment, the CDK is CDK4. In another embodiment, the CDK is CDK2 andCDK4.

A further aspect of the present invention provides the use of a compoundof formula (I), or a pharmaceutically acceptable salt or solvatethereof, or a physiologically functional derivative thereof, in thepreparation of a medicament for the treatment of cancer and malignanttumours.

The mammal requiring treatment with a compound of the present inventionis typically a human being.

The compounds of this invention may be made by a variety of methods,including standard chemistry. Any previously defined variable willcontinue to have the previously defined meaning unless otherwiseindicated. Illustrative general synthetic methods are set out below andthen specific compounds of the invention are prepared in the workingExamples.

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in part by the following synthesisschemes. In all of the schemes described below, it is well understoodthat protecting groups for sensitive or reactive groups are employedwhere necessary in accordance with general principles of chemistry.Protecting groups are manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley Et Sons). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selection ofprocesses as well as the reaction conditions and order of theirexecution shall be consistent with the preparation of compounds ofFormula (I). Those skilled in the art will recognize if a stereocenterexists in compounds of Formula (I). Accordingly, the present inventionincludes both possible stereoisomers and includes not only racemiccompounds but the individual enantiomers as well. When a compound isdesired as a single enantiomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be effected by any suitable method known in theart. See, for example, Stereochemistry of Organic Compounds by E. LElied, S. H. Wilen, and L N. Mander (Wiley-Interscience, 1994).

A general method for preparing compounds of the general formula (I)involves the reaction of a compound of general formula (A) with acompound of general formula (B). Formula (A) and formula (B) aredepicted in Scheme 1.

-   Q is alkyloxy, alkylthio or dialkylamino and integer a, and groups    R¹, R², and R³ are as defined above.

The general method can be readily carried out by mixing a compound ofgeneral formula (A) with a compound of general formula (B) in a suitablesolvent, optionally in the presence of a base, and heating the reactionmixture to about 50-200° C. Typically the solvent is a lower alcoholsuch as methanol, ethanol, isopropanol, 2-butoxyethanol and the like,and the base can be, for example, a sodium alkoxide, potassium carbonateor an amine base such as triethylamine.

As shown in Scheme 2, compounds of general formula (A) may beconveniently prepared by reacting a compound of general formula (C) witha dimethylformamide dialkylacetal, to give compounds of formula (A)wherein Q is Me₂N, or with a trialkyl orthoformate or a dialkoxymethylacetate, to give compounds of formula (A) wherein Q is an alkoxy group.Conveniently, the dimethylformamide dialkylacetal is dimethylformamidedimethyl acetal or dimethylformamide di-tert-butyl acetal and thereaction is carried out by mixing the compound of general formula (C)with the dimethylformamide dialkylacetal and optionally heating thereaction. Preferred trialkyl orthoformates include trimethylorthoformate and triethyl orthoformate. In a similar manner,diethoxymethyl acetate can be employed to prepare compounds of generalformula (A) wherein Q is EtO—. Integer a and groups R¹ and R² are asdefined above.

Compounds of general formula (C) can be prepared according to Scheme 3from compounds of general formula (D) and general formula (E) by acycloaddition procedure. Typically the cycloaddition procedure iscarried out by combining compounds of general formula (D) with compoundsof general formula (E) in a suitable solvent and treating the mixturewith a base. Optionally the reaction can be heated. Preferably thesolvent is dichloromethane, chloroform, acetonitrile, diethyl ether andthe like, and the base is an amine such as triethylamine,diisopropylethylamine or diazabicycloundecene (DBU). In anotherpreferred method, compounds of general formula (D) and (E) are combinedin a mixture of solvents and treated with a base. Preferably the solventmixtures are DMSO and water or methanol and water, and the base issodium hydroxide or potassium hydroxide. The groups R¹ and R², andinteger a are as defined above.

Compounds of general formula (D) are known in the literature and can beprepared as shown in Scheme 4 by oxidation of alcohols of generalformula (F) under conditions typically employed for the oxidation ofpropargylic alcohols. Group R¹ is as defined above.

Alternatively, compounds of general formula (D) can be preparedaccording to Scheme 5 by reaction of an ethyne of general formula (G)with a suitable base to form the ethynyl anion and treatment of saidanion with dimethyl acetamide. Preferably the base is an alkyl lithium,such as n-butyl lithium, or a lithium dialkylamide, such as lithiumdiisopropylamide (LDA). R¹ is as defined above.

As shown in Scheme 6, compounds of general formula (E) areN-aminopyridazines and are conveniently prepared by treatment of apyridazine of general formula (H) with an aminating reagent.Conveniently the aminating reagent is O-mesitylenesulfonylhydroxylamine(MSH) or hydroxylamine-O-sulfonic acid (HOSA). Preferably the aminatingagent is hydroxylamine-o-sulfonic acid in water with the addition of abuffer to control the pH of the reaction medium. Integer a and R² are asdefined above.

As shown in Scheme 7, compounds of general formula (I) can be convertedto alternate compounds of general formula (I). For example, compounds ofgeneral formula (J), wherein an R² group is a methoxy (OMe) substituentand is located at position 6, using the numbering system describedbelow, can be converted to compounds of general formula (K) wherein anR² is a hydroxyl group at position 6. Said conversion can be carried outby treatment of a compound of general formula (J) with an acid or a basein a suitable solvent and optionally heating the mixture. Preferably thebase is an amine such as morpholine. Preferably the acid is aqueoushydrogen iodide. Integer a, and groups R¹, R², and R³ are as definedabove.

The alcohol function in compounds of general formula (K) can be furthertransformed according to Scheme 8 by treatment with, for example,trifluoromethanesulfonic anhydride or N-phenyltrifluoromethylsulfonimideto afford a triflate. Said triflates are known in the literature asleaving groups and can be readily displaced by treatment with an aminein a suitable solvent to give compounds of general formula (L). Integera, and groups R¹, R², R³, R⁴, and R⁵ are as defined above.

-   Compounds of general formula (C) are similarly converted to    alternate compounds of general formula (C).

In Scheme 9, compounds of general formula (M) in which an R² group is amethoxy substituent, and is located at position 6, can be converted tothe corresponding hydroxy compound, of general formula (N), by treatmentwith an amine such as morpholine or an acid such as aqueous hydrogeniodide. Said hydroxy derivatives of general formula (N) can be convertedto triflates, of general formula (O), by treatment with atrifluoromethanesulfonylating agent such as trifluoromethanesulfonicanhydride or N-phenyltrifluoromethanesulfonimide. Triflates of generalformula (O) can be converted to amino, thio or ether derivatives bytreatment with amines, thiols or alcohols respectively, optionally inthe presence of a metal catalyst. Alternatively, triflates such as thoseof general formula (O) can be reacted with a transition metal catalystand a coupling partner to give compounds of general formula (P).Preferably the transition metal catalyst is a palladium or nickelcomplex. More preferably the catalyst is a palladium complex such astetrakis(triphenylphosphine)palladium(0). Coupling partners can bederivatives of tin, boron, zinc, aluminum, copper, magnesium, zirconium,and the like. Preferred coupling partners include triaklyltinderivatives or boron containing derivatives. Such reactions are welldocumented in the literature and are commonly referred to as Stillecouplings and Suzuki couplings respectively. Under said conditions,triflates such as those of general formula (O) can be converted tocompounds of general formula (P) wherein the group A can represent anaryl, heteroaryl, ethenyl, ethynyl and the like. It will be appreciatedby one skilled in the art that the aryl, heteroaryl, ethenyl, or ethynylgroup can be suitably substituted. Integer a, and groups R¹ and R² areas defined above.

As shown in Scheme 10, another method for the conversion of compounds ofgeneral formula (I) to alternative compounds of formula (I), compoundsof general formula (Q), wherein R³ is an alkylthio group, which can bereacted with an amine in a suitable solvent and optionally heated togive compounds of general formula (R). Preferred solvent for effectingthe reaction include lower alcohols, such as methanol, ethanol andisopropanol. Even more preferably the reaction is heated to about 150°C. in a sealed vessel.

A still more preferred method involves the oxidation of compounds ofgeneral formula (R) to the corresponding sulfoxide (S) or sulfone (T),followed by reaction with an amine in a suitable solvent with optionalheating. Preferred methods for effecting said oxidation involve the useof reagents typically employed for the oxidation of sulfur compoundssuch as hydrogen peroxide or m-chloroperoxybenzoic acid in an inertsolvent such as dichloromethane, acetonitrile and the like. Preferredsolvent for effecting the reaction with an amine include lower alcohols,such as methanol, ethanol and isopropanol. Even more preferably thereaction is heated to about 150° C. in a sealed vessel. Integer a andgroups R¹, R², R⁵, and R⁷ are as defined above.

As shown in Scheme 11, compounds of general formula (Q) can beconveniently prepared by treating a mixture of compounds of generalformula (U) and compounds of general formula (E) in a suitable solventwith a base and optionally heating the reaction mixture. Preferably thesolvent is a halogenated solvent, such as dichloromethane, and the baseis an amine, such as triethylamine, diazabicycloundecene (DBU) and thelike, or an alkali metal hydroxide, such as sodium hydroxide orpotassium hydroxide. Integer a and groups R¹ and R² are as definedabove.

As shown in Scheme 12, compounds of general formula (U) can beconveniently prepared by treating a compound of general formula (V),wherein B is a halogen such as iodide, bromide or chloride, or atriflate, with an ethyne of general formula (G) in a suitable solvent inthe presence of a palladium catalyst and optionally heating the reactionmixture. Preferably B is iodide and the palladium catalyst istetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine)palladium(II), and the like. Preferredsolvents include dichloromethane, tetrahydrofuran and the like.Compounds of general formula (V) are known in the literature.

Certain embodiments of the present invention will now be illustrated byway of example only. The physical data given for the compoundsexemplified is consistent with the assigned structure of thosecompounds.

EXAMPLES

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Standard single-letteror three-letter abbreviations are generally used to designate amino acidresidues, which are assumed to be in the L-configuration unlessotherwise noted. Unless otherwise noted, all starting materials wereobtained from commercial suppliers and used without furtherpurification. Specifically, the following abbreviations may be used inthe examples and throughout the specification:

g (grams); mg (milligrams); L (liters); mL (milliliters); μL(microliters); psi (pounds per square inch); M (molar); mM (millimolar);i.v. (intravenous); Hz (Hertz); MHz (megahertz); mol (moles); mmol(millimoles); RT (room temperature); min (minutes); h (hours); mp(melting point); TLC (thin layer chromatography); T_(r) (retentiontime); RP (reverse phase); MeOH (methanol); I-PrOH (isopropanol); TEA(triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroaceticanhydride); THF (tetrahydrofuran); DMSO (dimethylsulfoxide); EtOAc(ethyl acetate); DME (1,2-dimethoxyethane); DCM (dichloromethane); DCE(dichloroethane); DMF (N,N-dimethylformamide); DMPU (CDI(1,1-carbonyldiimidazole); (N,N'-dimethylpropyleneurea); IBCF (isobutylchloroformate); HOAc (acetic acid); HOSu (N-hydroxysuccinimide); HOBT(1-hydroxybenzotriazole); mCPBA EDC (meta-chloroperbenzoic acid;(ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC(9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide); CBZ(benzyloxycarbonyl); Ac (acetyl); atm (atmosphere); TMSE(2-(trimethylsilyl)ethyl); TMS (trimethylsilyl); TIPS(triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP(4-dimethylaminopyridine); Me (methyl); HPLC (high pressure liquidchromatography); BOP (bis(2-oxo-3-oxazolidinyl)phosphinic chloride);TBAF (tetra-n-butylammonium fluoride); Et (ethyl); tBu (tert-butyl);HOSA DEAD (diethylazodicarboxylate); (hydroxylamine sulfonic acid); DIEA(diisopropylethylamine).

All references to ether are to diethyl ether; brine refers to asaturated aqueous solution of NaCl. Unless otherwise indicated, alltemperatures are expressed in ° C. (degrees Centigrade). All reactionsconducted under an inert atmosphere at room temperature unless otherwisenoted.

¹H NMR spectra were recorded on a Varian VXR-300, a Varian Unity-300, aVarian Unity-400 instrument, or a General Electric QE-300. Chemicalshifts are expressed in parts per million (ppm, δ units)) relative toMe₄Si. Coupling constants are in units of hertz (Hz). Splitting patternsdescribe apparent multiplicities and are designated as s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broad).

Low-resolution mass spectra (MS) were recorded via LCMS on a MicromassZQ, ZMD, or QuattroMicro spectrometer; high resolution MS were obtainedusing a JOEL SX-102A spectrometer. All mass spectra were taken underelectrospray ionization (ESI), chemical ionization (CI), electron impact(EI), atmospheric pressure chemical ionization (APCI) or by fast atombombardment (FAB) methods. Infrared (IR) spectra were obtained on aNicolet 510 FT-IR spectrometer using a 1-mm NaCl cell. All reactionswere monitored by thin-layer chromatography on 0.25 mm E. Merck silicagel plates (60F-254), visualized with UV light, 5% ethanolicphosphomolybdic acid or p-anisaldehyde solution. Flash columnchromatography was performed on silica gel (230-400 mesh, Merck).Optical rotations were obtained using a Perkin Elmer Model 241Polarimeter. Melting points were determined using a Mel-Temp IIapparatus and are uncorrected.

The following examples describe the syntheses of intermediatesparticularly useful in the synthesis of compounds of Formula (I), (II),and (III):

Example 1 N-Cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) To a solution of(2E)-3-(dimethylamino)-1-pyrazolo[1,5-b]pyridazin-3-yl-2-propen-1-one(43 mg, 0.20 mmol) in DMF (2 mL) was addedN-cyclopropylguanidine.0.5H₂SO₄ (160 mg, 0.80 mmol) and potassiumcarbonate (110 mg, 0.80 mmol). The reaction was heated at an oil bathtemperature of 165° C. for about 18 hours. The mixture was cooled to RTand the solvent was removed in vacuo. The residue was dissolved inchloroform and filtered. The filtrate was purified by flash columnchromatography (0-10% gradient MeOH/CH₂Cl₂) to give the title compoundas a yellow solid (38 mg, 75%). ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.13 (dd,1H, J=9.0, 1.6 Hz), 8.77 (s, 1H), 8.53 (dd, 1H, J=4.4, 1.6 Hz), 8.24 (d,1H, J=5.2 Hz), 7.38 (m, 1H), 7.10 (d, 1H, J=5.2 Hz), 2.72 (m, 1H), 0.71(m, 2H), 0.47 (m, 2H), MS (ESI) (M+H)⁺ 253.

b)(2E)-3-(Dimethylamino)-1-pyrazolo[1,5-b]pyridazin-3-yl-2-propen-1-one.To a solution of 1-pyrazolo[1,5-b]pyridazin-3-ylethanone (8.5 g, 52.7mmol) in DMF (100 mL) was added dimethylformamide di-tert-butylacetal(16.1 g, 79.2 mmol). The reaction was heated at an oil bath temperatureof 100° C. for about 4 hours. The solvent was removed in vacuo. Theresidue was triturated with diethylether to give the title compound as abrown solid (8 g, 70%). ¹H-NMR (300 MHz, d⁶-DMSO) δ 8.76 (dd, 1H,J=10.0, 2.0 Hz), 8.74 (s, 1H), 8.61 (dd, 1H, J=4.0, 2.0 Hz), 7.74 (d,1H, J=12 Hz), 7.44 (dd, 1H, J=10.0, 4.0 Hz), 5.87 (d, 1H, J=12 Hz), 3.18(bs, 3H), 2.97 (bs, 3H); MS (ESI) (M+H)⁺ 217.

c) 1-Pyrazolo[1,5-b]pyridazin-3-ylethanone. To a slurry of1-aminopyridazinium iodide (16 g, 72 mmol) in CH₂Cl₂ (200 mL) was added3-butyne-2-one (2.4 g, 36 mmol). The reaction flask was cooled in an icebath at 4° C. and a solution of KOH (5.0 g, 89 mmol) in water (100 mL)was added in one portion. The mixture was stirred at RT for about 4hours. The organic layer was separated and the aqueous layer wasextracted with CH₂Cl₂ (2×200 mL). The combined organic layers were dried(MgSO₄), filtered and concentrated in vacuo. The residue was trituratedwith diethyl ether to give the title compound as a red solid (4.0 g,69%). ¹H-NMR (300 MHz, CDCl₃) δ 8.78 (dd, 1H, J=9.0, 2.0 Hz), 8.51 (dd,1H, J=4.4, 2.0 Hz), 8.47 (s, 1H), 7.35 (dd, 1H, J=9.0, 4.4 Hz), 2.63 (s,3H); MS (ESI) (M+H)⁺ 162.

d) 1-Aminopyridazinium iodide. Hydroxylamine-O-sulfonic acid (13.1 g,115 mmol) was dissolved in water (25 mL) and the reaction flask wascooled in an icebath at 10° C. Aqueous KHCO₃ (48 mL, 2.4 M) was addeduntil the solution was at pH 5.0. Pyridazine (6.2 g, 77 mmol) was addedin one portion and the flask was heated to 70° C. for about 1 hour. ThepH was adjusted to 7.0 by the addition of aqueous KHCO₃ (approx. 10 mL,2.4M). The reaction was cooled to 40° C. and the mixture was allowed tostir for about 1 hour. Potassium iodide (12.8 g, 77 mmol) in water (25mL) was added. The solvent was removed in vacuo followed by the additionof 5% methanol in ethanol (100 mL). The solids were collected byfiltration and dried in vacuo to give the title compound as a yellowsolid (10.5 g, 61%). ¹H-NMR (300 MHz, d⁶-DMSO) δ 8.85 (bs, 2H), 9.27 (d,1H, J=5.2 Hz), 9.12 (d, 1H, J=6.3 Hz), 8.49 (ddd, 1H, J=8.1, 6.3, 2.1Hz), 8.14 (dd, 1H, J=8.1, 5.2 Hz).

e) N-Cyclopropylguanidine.0.5H₂SO₄. To a solution of O-methylisoureahydrogensulfate (50.0 g, 290 mmol) in water (150 mL) was addedcyclopropyl amine (33.0 g, 581 mmol). The mixture was heated at an oilbath temperature of 100° C. for about 14 hours. The water was removed invacuo. Ethanol (150 mL) was added and the solids isolated by filtration.The solids were dried under vacuum (1 torr) for about 18 hours to givethe title compound as a white powder (47.6 g, 42%). ¹H-NMR (300 MHz,d⁶-DMSO) δ 2.0 (m, 1H), 0.20 (m, 2H), 0.10 (m, 2H).

Example 2N-Cyclopropyl-N-methyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a). To a solution ofN-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine (25 mg,0.1 mmol) in DMF (2 mL) was added sodium hydride (6 mg, 0.25 mmol) andmethyl iodide (0.013 mL, 0.15 mmol). The reaction was allowed to stirfor about 1 hour. The reaction was concentrated in vacuo. Water (10 mL)was added and the aqueous layer was extracted with EtOAc (2×30 mL). Thecombined organic layers were dried (MgSO₄) filtered and concentrated invacuo. The residue was triturated with diethylether to give the titlecompound as light orange solid (20 mg, 80%). ¹H-NMR (400 MHz, CDCl₃) δ9.07 (d, 1H, J=8.8 Hz), 8.46 (s, 1H), 8.35 (m, 2H) 7.12 (dd, 1H, J=8.8,4.4 Hz), 6.89 (d, 1H, J=5.6 Hz), 3.23 (s, 3H), 2.85 (m, 1H), 0.94 (m,2H), 0.73 (m, 2H); MS (ESI) (M+H)⁺ 267.

Example 34-Pyrazolo[1,5-b]pyridazin-3-yl-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-2,2,2-trifluoroethylguanidine.0.5H₂SO₄ was obtained the title compoundas a yellow solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 8.81 (s, 1H), 8.54 (dd,1H, J=4.4, 2.0 Hz), 8.31 (d, 1H, J=5.6 Hz), 7.80 (bm, 1H), 7.40 (dd, 1H,J=8.8, 4.4 Hz), 7.21 (d, 1H, J=4.4 Hz), 4.17 (m, 2H); MS (APCI) (M+H)⁺295.

b) N-(2,2,2-Trifluoroethyl)guanidine.0.5H₂SO₄. In a similar manner asdescribed in Example 1e, from 2,2,2-trifluroethyl amine was obtained thetitle compound (Tetrahedron Lett (1993), 34-(21), 3389) as a brownsolid.

Example 4 N-Phenyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromphenylguanidine.HNO₃ was obtained the title compound as a brown solid.¹H-NMR (300 MHz, d⁶-DMSO) δ 9.61 (s, 1H), 9.2 (d. 1He J=9.0 Hz), 8.93(s, 1H), 8.63 (d, 1H, J=2.9 Hz), 8.50 (d, 1H, J=5.2 Hz), 7.78 (d, 2H,J=8.1 Hz), 7.49 (dd, 1H, J=9.0, 4.1 Hz), 7.37 (m, 3H), 7.02 (t, 1H,J=7.3 Hz); MS (ESI) (M+H)⁺ 289.

Example 5N-(4-Chlorophenyl)pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(4-chlorophenyl)guanidine.HNO₃ was obtained the title compound as abrown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.76 (s, 1H), 9.19 (d, 1H,J=8.8 Hz), 8.94 (s, 1H), 8.64 (d, 1H, J=2.8 Hz), 8.51 (d, 1H, J=8.8 Hz),7.84 (d, 2H, J=8.8 Hz), 7.53 (dd, 1H, J=9.2, 4.5 Hz), 7.42 (m, 3H); MS(ESI) (M+H)⁺ 323.

Example 6 N-0Fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(4-fluorophenyl)guanidine.HNO₃ was obtained the title compound as ayellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.63 (s, 1H), 9.15 (d, 1H,J=8.7 Hz), 8.92 (s, 1H), 8.64 (dd, 1H, J=4.5, 1.8 Hz), 8.48 (d, 1H,J=5.3 Hz), 7.78 (dd, 2H, J=9.0, 5.0 Hz), 7.50 (dd, 1H, J=9.1, 4.6 Hz),7.40 (d, 1H, J=5.3 Hz), 7.21 (t, 2H, J=8.9 Hz); MS (ESI) (M+H)⁺ 307.

Example 73-[(4-Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile

a) In a similar manner as described in Example 1a, fromN-(3-cyanophenyl)guanidine.HNO₃ was obtained the title compound as ayellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.99 (s, 1H), 9.17 (d, 1H,J=9.0 Hz), 8.96 (s, 1H), 8.66 (dd, 1H, J=4.4, 1.6 Hz), 8.58 (d, 1H,J=5.3 Hz), 8.41 (s, 1H), 7.97 (d, 1H, J=8.2 Hz); 7.60-7.44 (m, 4H); MS(APCI) (M+H)⁺ 314.

b) N-((3-Cyanophenyl)guanidine.HNO₃. To a solution of3-aminobenzonitrile (3.31 g, 28 mmol) in ETOH (28 mL) was addedcyanamide (2.5 mL of a 50% w/w solution in water). HNO₃ (1.98 mL, 14.2M) is added dropwise. The mixture was heated at an oil bath temperatureof 100° C. for about 3 hours. The flask was allowed to cool to RT. Et₂O(20 mL) was added and the solids isolated by filtration. The solids weredried under vacuum (1 torr) for about 18 hours to give the titlecompound as a beige powder (2.9 g, 46%). ¹H-NMR (300 MHz, d⁶-DMSO) δ9.80 (s, 1H), 7.77 (m, 2H), 7.69-7.57 (m, 6H); MS (ESI) (M+H)⁺ 161.

Example 84-[(4-Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzoic Acid

a) In a similar manner as described in Example 1a,4-{[amino(imino)methyl]amino}benzoic acid.HCl was obtained the titlecompound as a yellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.99 (s, 1H),9.25 (d, 1H, J=9.0 Hz), 8.96 (s, 1H), 8.65 (dd, 1H, J=4.5, 2.6 Hz), 8.57(d, 1H, J=5.2 Hz), 7.93 (m, 4H), 7.53 (dd, 1H, J=8.9, 4.4 Hz), 7.50 (d,1H, J=5.5 Hz); MS (APCI) (M+H)⁺ 333.

Example 94-Pyrazolo[1,5-b]pyridazin-3-yl-N-[3-(trifluoromethyl)phenyl]-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-(trifluoromethyl)phenyl]guanidine was obtained the title compoundas a brown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.98 (s, 1H), 9.17 (d, 1H,J=8.9 Hz), 8.95 (s, 1H), 8.65 (bs, 1H), 8.57 (d, 1H, J=5.4 Hz), 8.32(bs, 1H), 8.00 (d, 1H, J=8.1 Hz), 7.59 (t, 1H, J=8.0 Hz), 7.48 (m, 2H),7.34 (d, 1H, J=8.1 Hz); MS (ESI) (M+H)⁺ 357.

Example 10N-(3-Nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(3-nitrophenyl)guanidine was obtained the title compound as a brownsolid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 10.15 (s, 1H), 9.18 (d, 1H, J=8.9Hz), 8.97 (s, 1H), 8.93 (s, 1H), 8.66 (d, 1H, J=4.4 Hz), 8.60 (d, 1H,J=5.1 Hz), 8.11 (d, 1H, J=8.1 Hz), 7.85 (d, 1H, J=8.1 Hz), 7.64 (t, 1H,J=8.1 Hz), 7.50 (m, 2H); MS (ESI) (M+H)⁺ 357.

b) N-(3-Nitrophenyl)guanidine.HCl. In a similar manner as described inExample 1e, from 3-nitrophenyl aniline was obtained the title compound(Anal. Biochem. (1999), 276(2), 251) as a brown solid.

Example 11N-(2-Chlorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(2-chlorophenyl)guanidine was obtained the title compound as a brownsolid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.06 (s, 1H), 8.90 (s, 1H), 8.84 (d,1H, J=9.0 Hz), 8.60 (bs, 1H), 8.44 (d, 1H, J=5.2 Hz), 7.81 (d, 1H, J=8.1Hz), 7.59 (d, 1H, J=7.9 Hz), 7.39 (m, 3H), 7.26 (t, 1H, J=7.6 Hz); MS(ESI) (M+H)⁺ 323.

b) N-(2-Chlorophenyl)guanidine.HCl. Prepared from 2-chlorophenyl anilineas described in (J. Med. Chem. (1996), 39(20), 4017).

Example 12N-(4-Methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(4-methoxyphenyl)guanidine was obtained the title compound as a brownsolid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.41 (s, 1H), 9.15 (bs; 1H), 8.90 (s,1H), 8.62 (d, 1H, J=2.6 Hz), 8.44 (d, 1H, J=5.3 Hz), 7.64 (d, 2H, J=8.9Hz), 7.47 (dd, 1H, J=9.1, 4.5 Hz), 733 (d, 1H, J=5.2 Hz), 6.95 (d, 1H,J=8.9 Hz), 3.78 (s, 3H); MS (ESI) (M+H)⁺ 319.

Example 134-Pyrazolo[1,5-b]pyridazin-3-yl-N-(3,4,5-trimethoxyphenyl)-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(3,4,5-trimethoxyphenyl)guanidine was obtained the title compound as abrown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.50 (s, 1H), 9.21 (d, 1H,J=9.7 Hz), 8.92 (s, 1H), 8.63 (d, 1H, J=2.7 Hz), 8.50 (d, 1H, J=5.2 Hz),7.47 (dd, 1H, J=9.1, 4.5 Hz), 7.38 (d, 1H, J=5.2, 4.5 Hz), 7.18 (s, 2H);MS (ESI) (M+H)⁺ 379.

b) N-(3,4,5-Trimethoxyphenyl)guanidine.HNO₃. In a similar manner asdescribed in Example 7b, from 3,4,5-trimethoxy aniline was obtained thetitle compound (J. Med. Chem. (1975), 18(11), 1077) as a brown solid.

Example 14N-[3-(1,3-Oxazol-5-yl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-(1,3-oxazol-5-yl)phenyl]guanidine was obtained the title compoundas a brown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.78 (s, 1H), 9.18 (d, 1H,J=8.9 Hz), 8.95 (s, 1H), 8.64 (d, 1H, J=3.1 Hz), 8.55 (d, 1H, J=5.2 Hz),8.46 (s, 1H), 8.24 (s, 1H), 7.75 (d, 1H, J=7.9 Hz), 7.67 (s, 1H),7.49-7.39 (m, 3H), 7.35 (dd, 1H, J=9.0, 4.5 Hz); MS (ESI) (M+H)⁺ 356.

b) N[3-(1,3-Oxazol-5-yl)phenyl]guanidine.HNO₃. In a similar manner asdescribed in Example 7b, from 3-(1,3-oxazol-5-yl)aniline was obtainedthe title compound as a brown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.70(s, 1H), 8.52 (s, 1H), 7.80 (s, 1H), 7.70-7.43 (m, 7H), 7.27 (d, 1H,J=7.9 Hz); MS (ESI) (M+H)⁺ 203.

Example 15N-(4-Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1H-benzimidazol-6-amine

a) In a similar manner as described in Example 1a, fromN-(1H-benzimidazol-6-yl)guanidine.HNO₃ was obtained the title compoundas a brown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 12.35 (bs, 1H), 9.59 (s,1H), 9.21 (d, 1H, J=9.2 Hz), 8.93 (s, 1H), 8.64 (d, 1H, J=2.7 Hz), 8.50(d, 1H, J=5.2 Hz), 8.18 (s, 1H), 8.16 (s, 1H), 7.58 (d, 1H, J=8.5 Hz),7.45-7.41 (m, 2H), 7.37 (d, 1H, J=5.2 Hz); MS (ESI) (M+H)⁺ 329.

b) N-(1H-Benzimidazol-6-yl)guanidine.HNO₃. In a similar manner asdescribed in Example 7b, from 1H-benzimidazol-6-amine was obtained thetitle compound as a brown solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.76 (s,1H), 9.40 (s, 1H), 7.85 (d, 1H, J=8.8 Hz), 7.69 (d, 1H, J=1.8 Hz), 7.42(bs, 4H), 7.37 (dd, 1H, J=8.8, 1.8 Hz); MS (ESI) (M+H)⁺ 176.

Example 16N-(4Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-benzoxazol-2-amine

a) In a similar manner as described in Example 1a, fromN(1,3-benzoxazol-2-yl)guanidine was obtained the title compound as abrown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 11.68 (s, 1H), 10.23 (d, 1H,J=9.1 Hz), 9.02 (s, 1H), 8.68-8.65 (m, 2H), 7.73-7.62 (m, 4H), 7.38-7.25(m, 2H); MS (ESI) (M+H)⁺ 0.330.

Example 17N-(6-Chloro-1H-benzimidazol-2-yl)-N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amine

a) In a similar manner as described in Example 1a, fromN-(6-Chloro-1H-benzimidazol-2-yl)guanidine was obtained the titlecompound as a brown solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 12.20 (s, 1H),11.32 (s, 1H), 9.50 (d, 1H, J=8.0 Hz), 8.96 (s, 1H), 8.62 (dd, 1H,J=4.4, 1.8 Hz), 8.59 (d, 1H, J=5.5 Hz), 7.56 (d, ₁H, J=5.5 Hz), 7.48(dd, 1H, J=9.0, 4.4 Hz), 7.53 (m, 1H), 7.40 (m, 1H), 7.06 (m, 1H); MS(ESI) (M+H)⁺ 363.

Example 18N-(4-Chlorobenzyl)-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(4-chlorobenzyl)guanidine was obtained the title compound as a brownsolid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.20 (bs, 1H), 8.78 (bs, 1H), 8.54(bs, 1H), 8.27 (d, 1H, J=5.1 Hz), 7.82 (m, 1H), 7.39 (m; 5H), 7.12 (d,1H, J=5.4 Hz), 4.54 (s, 2H); MS (ESI) (M+H)⁺ 337.

b) N-(4-Chlorobenzyl)guanidine.HO₂-CCF₃. Prepared from4-chlorobenzylamine as described in (J. Med. Chem. (1975), 18(3), 304).

Example 19N¹,N¹-Dimethyl-N³-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-propanediamine

a) In a similar manner as described in Example 1a, fromN-[3-(dimethylamino)propyl]guanidine.0.5H₂SO₄ was obtained the titlecompound as a yellow solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.10 (bs, 1H),8.76 (s, 1H),8.53 (dd, 1H, J=4.4, 2.0 Hz), 8:21 (d, 1H, J=5.2 Hz), 7.38(dd, 1H, J=9.2, 4.4 Hz), 7.21 (bs, 1H), 7.05 (d, 1H, J=5.2 Hz), 2.87 (m,2H), 2.50 (m. 2H), 2.27 (bs, 6H), 1.73 (m, 2H); MS (APCI) (M+H)⁺ 298.

b) N-[3-(Dimethylamino)propyl]guanidine.0.5H₂SO₄. In a similar manner asdescribed in Example 1e, from N-3-(dimethylamino)propylamine wasobtained the title compound as a white solid. ¹H-NMR (300 MHz, D₂O) δ3.19 (t, 2H, J=6.6 Hz), 3.04 (m, 2H), 2.75 (s, 6H), 1.93 (m, 2H).

Example 20N-[3-(4Morpholinyl)propyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-(4-morpholinyl)propyl]guanidine.0.5H₂SO₄ was obtained the titlecompound as a yellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.10 (bs, 1H),8.84 (s, 1H), 8.61 (dd, 1H, J=4.2, 2.0 Hz), 8.29 (d, 1H, J=5.1 Hz), 7.46(dd, 1H, J=9.0, 4.2 Hz), 7.27 (bs, 1H), 7.11 (d, 1H, J=5.1 Hz), 3.58 (m,2H), 3.40 (m, 2H), 3.31 (m, 2H), 2.54 (m, 2H), 2.40 (m, 4H), 1.78 (m,2H); MS (APCI) (M+H)⁺ 340.

b) N-[3-(4-Morpholinyl)propyl]guanidine.0.5H₂SO₄. In a similar manner asdescribed in Example 1e, from N-3-(4-morpholinyl)propylamine wasobtained the title compound (Bioorg. Med. Chem. Lett (1997), 7(6), 675)as a white solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 3.58 (bm, 4H), 3.15 (m,4H), 3.05 (m, 4H), 1.85 (m, 2H).

Example 21N-[3-(4Methyl-1-piperazinyl)propyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-(4-methyl-1-piperazinyl)propyl]guanidine.0.5H₂SO₄ was obtained thetitle compound as a yellow solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.00 (bs,1H), 8.76 (s, 1H), 8.53 (dd, 1H, J=4.4, 2.0 Hz), 8.21 (d, 1H, J=5.6 Hz),7.37 (dd, 1H, J=8.8, 4.0 Hz), 7.20 (bs, 1H), 7.03 (d, 1H, J=5.2 Hz),3.32 (m, 6H), 2.34 (m, 6H), 2.11 (m, 3H), 1.68 (m, 2H); MS (APCI)(M+H)⁺353.

b) N-[3-(4-Methyl-1-piperazinyl)propyl]guanidine.0.5H₂SO₄ In a similarmanner as described in Example 1e, fromN-3-(4-methyl-1-piperazinyl)propylamine was obtained the title compound(Bioorg. Med. Chem. Lett. (1997), 7(6), 675) as a white solid.

Example 221-{3-[(Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]propyl}-2-pyrrolidinone

a) In a similar manner as described in Example 1a, fromN-[3-(2-oxo-1-pyrrolidinyl)propyl]guanidine.HO₂-CCF₃ was obtained thetitle compound as a yellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.08 (bs,1H), 8.84 (s, 1H), 8.61 (m, 1H), 8.30 (d, 1H, J=5.1 Hz), 7.47 (dd, 1H,J=8.9, 4.4 Hz), 7.22 (bs, 1H), 7.13 (d, 1H, J=5.3 Hz), 3.35 (m, 4H),2.52 (m, 2H), 2.23 (m, 2H), 1.95 (m, 2H), 1.79 (m, 2H); MS (ESI)(M+H)⁺338.

b) N-[3-(2-Oxo-1-pyrrolidinyl)propyl]guanidine.HO₂CCF₃. In a similarmanner as described in Example 1e, from1-(3-aminopropyl)-2-pyrrolidinone was obtained the title compound as awhite solid.

Example 23N-[3-Chloro-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-chloro-4-(4-methyl-1-piperazinyl)phenyl]guanidine.HNO₃ was obtainedthe title compound as a yellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.95(s, 1H), 9.16 (d, 1H, J=8.6 Hz), 8.93 (s, 1H), 8.64 (m, 1H), 8.50 (d,1H, J=2.4 Hz), 7.54 (dd, 1H, J=8.6, 2.4 Hz), 7.49 (dd, 1H, J=9.1, 4.4Hz), 7.41 (d, 1H, J=5.2 Hz), 7.19 (d, 1H, J=8.8 Hz), 2.95 (m, 4H), 2.51(m, 4H), 2.28 (s, 3H); MS (ESI) (M+H)⁺ 421.

b) N[3-Chloro-4-(4-methyl-1-piperazinyl)phenyl]guanidine.HNO₃. In asimilar manner as described in Example 7b, from3-chloro-4-(4-methyl-1-piperazinyl)aniline was obtained the titlecompound as a white solid.

Example 24N-[4-(4-Methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl was obtained the titlecompound as a yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.89 (d, 1H, J=9.0Hz), 8.52 (s, 1H), 8.40 (m, 2H), 7.49 (d, 2H, J=8.8 Hz), 7.30 (s, 1H),7.12 (dd, 1H, J=9.0, 4.3 Hz), 7.04 (m, 2H), 6.95 (m, 1H), 3.26 (m, 4H),2.66 (m, 4H), 2.42 (s, 3H); MS (ESI) (M+H)⁺ 387.

b) N-[4-(4-Methyl-1-piperazinyl)phenyl]guanidine.HCl. Prepared from4-(4-methyl-1-piperazinyl)aniline as described in (J. Med. Chem. (1993),36(19), 2716).

Example 25N-[3-Methyl-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]guanidine.HNO₃ was obtainedthe title compound as a brown solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.35(s, 1H), 9.11 (d, 1H, J=8.2 Hz), 8.86 (s, 1H), 8.58 (dd, 1H, J=4.6, 1.9Hz), 8.41 (d, 1H, J=5.1 Hz), 7.55 (d, 1H, J=2.4 Hz), 7.43-7.40 (m, 2H),7.30 (d, 1H, J=5.3 Hz), 7.00 (d, 1H, J=8.6 Hz), 2.83-2.81 (m, 4H),2.50-2.48 (m, 4H), 2.24 (m, 6H); MS (ESI) (M+H)⁺ 401.

b) N[3-Methyl-4-(4-methyl-1-piperazinyl)phenyl]guanidine.HNO₃. In asimilar manner as described in Example 7b, from3-methyl-4-(4-methyl-1-piperazinyl)aniline was obtained the titlecompound as a brown solid.

Example 26N-[4-(4Methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]guanidine.HNO₃was obtained the title compound as a yellow solid. ¹H-NMR (400 MHz,d⁶-DMSO) δ 9.80 (s, 1H), 9.10 (d, 1H, J=8.1 Hz), 8.89 (s, 1H), 8.60 (dd,1H, J=4.4, 2.0 Hz), 8.48 (d, 1H, J=5.3 Hz), 8.14 (d, 1H, J=2.4 Hz), 7.93(d, 1H, J=8.8 Hz), 7.53 (d, 1H, J=8.8 Hz), 7.42 (m, 2H), 2.284 (m, 4H),2.48 (m, 4H), 2.24 (s, 3H); MS (ESI) (M+H)⁺ 455.

b) N-[4-(4-Methyl-1-piperazinyl)-3-(trifluoromethyl) phenyl]guanidine.HNO₃. In a similar manner as described in Example 7b, from4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenylamine was obtainedthe title compound as a white solid.

Example 27N-[3-Chloro-4-(4-morpholinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[3-chloro-4-(4-morpholinyl)phenyl]guanidine.HNO₃ was obtained thetitle compound as a yellow solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.67 (s,1H), 9.17 (d, 1H, J=9.3 Hz), 8.93 (s, 1H), 8.64 (dd, 1H, J=4.4, 1.8 Hz),8.51 (d, 1H, J=5.2 Hz), 8.06 (d, 1H, J=2.5 Hz), 7.58 (dd, 1H, J=8.7, 2.4Hz), 7.50 (dd, 1H, J=9.1, 4.5 Hz), 7.42 (d, 1H, J=5.4 Hz), 7.21 (d, 1H,J=8.6 Hz), 3.77 (m, 4H), 2.97 (m, 4H); MS (ESI) (M+H)⁺ 408.

b) N-[3-Chloro-4-(4-morpholinyl)phenyl]guanidine.HNO₃. In a similarmanner as described in Example 7b, from3-chloro-4-(4-morpholinyl)aniline was obtained the title compound as abrown solid. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.50 (s, 1H), 7.37 (bs, 5H),7.23 (s, 2H), 3.77 (m, 4H), 2.99 (m, 4H); MS (ESI) (M+H)⁺ 255.

Example 28N-[{4-(Diethylamino)methyl]phenyl}-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]guanidine.HNO₃was obtained the title compound as a yellow solid. ¹H-NMR (400 MHz,d⁶-DMSO) δ 9.75 (bs, 1H), 9.40 (bs, 1H), 9.17 (d, 1H, J=8.8 Hz), 8.89(s, 1H), 8.62 (d, 1H, J=2.7 Hz), 8.48 (d, 1H, J=5.1 Hz), 7.82 (bs, 2H),7.45-7.39 (m, 3H), 4.24 (bs, 2H), 3.22 (bs, 4H), 1.20 (bs, 6H); MS (ESI)(M+H)⁺ 374.

b) N-{4-[(Diethylamino)methyl]phenyl}guanidine.HNO₃. In a similar manneras described in Example 7b, from 4-[(diethylamino)methyl]aniline wasobtained the title compound as a brown solid.

Example 29N-[2-(Diethylamino)ethyl]-4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzamide

a) In a similar manner as described in Example 1a, from4-{[amino(imino)methyl]amino}-N-[2-(diethylamino)ethyl]benzamide.HNO₃was obtained the title compound as a yellow solid. ¹H-NMR (300 MHz,d⁶-DMSO) δ 9.89 (s, 1H), 9.24 (d, 1H, J=7.5 Hz), 8.95 (s, 1H), 8.66 (dd,1H, J=4.5, 1.9 Hz), 8.56 (d, 1H, J=5.2 Hz), 7.90-7.83 (m, 4H), 7.52 (dd,1H, J=9.0, 4.5 Hz), 7.47 (d, 1H, J=5.4 Hz), 5.42 (bs, 2H), 3.35 (bs,2H), 2.60 (bs, 4H), 1.02 (bs, 6H); MS (ESI) (M+H)⁺ 431.

b) 4-{[Amino(imino)methyl]amino}-N-[2-(diethylamino)ethyl]benzamide.HNO₃. In a similar manner as described in Example 7b, from4-amino-N-[2-(diethylamino)ethyl]benzamide was obtained the titlecompound as a brown solid.

Example 30N-Cyclopropyl(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) To a solution(2E)-3-(dimethylamino)-1-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one(50 mg, 0.22 mmol) in DMF (2.5 mL) was addedN-cyclopropylguanidine.0.5H₂SO₄ (130 mg, 0.66 mmol) and potassiumcarbonate (152 mg, 1.10 mmol). The reaction was heated at an oil bathtemperature of 135° C. for about 18 hours. The mixture was cooled to RTand the solvent was removed in vacuo. The residue was dissolved inchloroform and filtered. The filtrate was concentrated in vacuo thendisolved in CH₂Cl₂ and triturated with diethylether to give the titlecompound as a yellow solid (22 mg, 38%). ¹H-NMR (300 MHz, CDCl₃) δ 9.02(d, 1H, J=8.8 Hz), 8.39 (d, 1H, J=5.2 Hz), 8.35 (dd, 1H, J=4.4, 2.0 Hz),7.15 (dd, 1H, J=8.8, 4.4 Hz), 6.94 (d, 1H, J=5.3 Hz), 5.45 (s, 1H), 2.89(m, 1H), 2.83 (s, 3H), 0.91 (m, 2H), 0.68 (m, 2H); MS (ESI) (M+H)⁺ 267.

b)(2E)-3-(Dimethylamino)-1-(2-methylpyrazolo[1,5-pyridazin-3-yl)-2-propen-1-one.1-(2-Methylpyrazolo[1,5-b]pyridazin-3-yl)ethanone (165 mg, 0.95 mmol)was added to DMF dimethylacetal (6.0 mL). The reaction was heated at anoil bath temperature of 120° C. for about 3 days. The solvent wasremoved in vacuo. The residue was triturated with diethylether to givethe title compound as a brown solid (60 mg, 26%). ¹H-NMR (300 MHz,CDCl₃) δ 8.68 (dd, 1H, J=9.1, 2.0 Hz), 8.32 (dd, 1H, J=4.5, 2.0 Hz),7.83 (d, 1H, J=12.4 Hz), 7.14 (dd, 1H, J=9.1, 4.5 Hz), 5.59 (d, 1H,J=12.4 Hz), 2.91-3.10 (bm, 6H), 2.81 (s, 3H); MS (APCI) (M+H)⁺ 231.

c) 1-(2-Methylpyrazolo[1,5-b]pyridazin-3-yl)ethanone. To a slurry of1-aminopyridazinium iodide (709 mg, 3.2 mmol) in DMSO (6.0 mL) was added3-pentyne-2-one (1.45 g, 6.4 mmol) as a solution (2:1 by ¹H NMR) in THF.The reaction flask was cooled in an ice bath at 4° C. then KOH (178 mg,3.2 mmol) and K₂-CO₃ (219 mg, 1.59 mmol) were added in one portion. Thebath was removed and the mixture was stirred at RT for about 4 hours.Water was added (20 mL). The organic layer was separated and the aqueouslayer was extracted with CH₂Cl₂ (3×20 mL). The combined organic layerswere dried (MgSO₄), filtered and concentrated in vacuo. The residue wastriturated with diethyl ether and EtOAc to give the title compound as ared solid (165 mg, 29%). ¹H-NMR (300 MHz, CDCl₃) δ 8.69 (dd, 1H, J.=9.1,2.0 Hz), 8.42 (dd, 1H, J=4.7, 2.0 Hz), 7.29 (dd, 1H, J=9.1, 4.7 Hz),2.82 (s, 3H), 2.62 (s, 3H).

d) 3-Pentyn-2-one. Propyne was condensed in THF at −78° C. untilsaturated. nBuLi (10 mL 25 mmol) was added in one portion. The reactionmixture was stirred for 10 minutes then dimethylacetamide (2.3 mL, 25mmol) was added. The cooling bath was removed an the mixture was stirredat RT for about 1 hour. Water was added (100 mL) followed by theaddition of diethylether (200 mL). The combined organic layers weredried (MgSO₄), filtered and concentrated in vacuo to about 2 mL. The THFsolution was used in the next step.

Example 31N-Cyclopropyl-4-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) To a solution(2E)-3-(dimethylamino)-1-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one(75 mg, 0.31 mmol) in DMF (2.0 mL) was addedN-cyclopropylguanidine.0.5H₂SO₄ (181 mg, 0.92 mmol) and potassiumcarbonate (212 mg, 1.54 mmol). The reaction was heated at an oil bathtemperature of 135° C. for about 18 hours. The mixture was cooled to RTand the solvent was removed in vacuo. The residue was dissolved inchloroform and filtered. The filtrate was concentrated in vacuo thendisolved in CH₂Cl₂ and triturated with diethylether and hexanes to givethe title compound as an orange solid (32 mg, 360% o). ¹H-NMR (300 MHz,CDCl₃) δ 8.96 (d, 1H, J=8.7 Hz), 8.38 (d, 1H, J=5.4 Hz), 8.34 (dd, 1H,J=4.4, 1.9 Hz), 7.14 (dd, 1H, J=9.0, 4.5 Hz), 6.92 (d, 1H, J=5.4 Hz),5.47 (s, 1H), 3.23 (q, 2H, J=7.5 Hz), 2.88 (m, 1H), 1.50 (t, 3H, J=7.5Hz), 0.91 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)⁺ 281.

b)(2E)-3-(Dimethylamino)-1-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one.1-(2-Ethylpyrazolo[1,5-b]pyridazin-3-yl)ethanone (350 mg, 1.85 mmol) wasadded to DMF dimethylacetal (9.0 mL). The reaction was heated at an oilbath temperature of 120° C. for about 3 days. The solvent was removed invacuo. The residue was triturated with diethylether to give the titlecompound as a brown solid (75 mg, 17%). The crude material was usedwithout purification in the next step.

c) 1-(2-Ethylpyrazolo[1,5-b]pyridazin-3-yl)ethanone. To a slurry of1-aminopyridazinium iodide (1.60 g, 7.2 mmol) in DMSO (14.0 mL) wasadded 3-hexyne-2-one (1.57 mL, 14.4 mmol). The reaction flask was cooledin an ice bath at 4° C. then KOH (403 mg, 7.2 mmol) and K₂-CO₃ (500 mg,3.6 mmol) were added in one portion. The bath was removed and themixture was stirred at RT for about 1 hour. Water was added (60 mL). Theorganic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo. The residue was triturated withdiethyl ether and EtOAc to give the title compound as a red solid (350mg, 26%). ¹H-NMR (300 MHz, CDCl₃) δ 8.67 (dd, 1H, J=9.0, 2.0 Hz), 8.42(dd, 1H, J=4.5, 2.0 Hz), 7.29 (dd, 1H, J=9.0, 4.5 Hz), 3.23 (q, 2H,J=7.5 Hz), 2.66 (s, 3H), 1.50 (t, 3H, J=7.5 Hz); MS (ESI) (M+H)⁺ 245.

Example 324-(2-Butylpyrazolo[1,5-b]pyridazin-3-yl)-N-cyclopropyl-2-pyrimidinamine

a) To a solution(2E)-3-(dimethylamino)-1-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one(50 mg, 0.22 mmol) in DMF (2.5 mL) was addedN-cyclopropylguanidine.0.5H₂SO₄ (130 mg, 0.66 mmol) and potassiumcarbonate (152 mg, 1.10 mmol). The reaction was heated at an oil bathtemperature of 135° C. for about 18 hours. The mixture was cooled to RTand the solvent was removed in vacuo. The residue was dissolved inchloroform and filtered. The filtrate was concentrated in vacuo thendisolved in CH₂Cl₂ and triturated with diethylether to give the titlecompound as a yellow solid (22 mg, 38%). ¹H-NMR (400 MHz, CDCl₃) δ 8.87(d, 1H, J=7.2 Hz), 8.30 (d, 1H, J=5.2 Hz), 8.24 (dd, 1H, J=4.4, 2.0 Hz),7.03 (dd, 1H, J=9.0, 4.4 Hz), 6.81 (d, 1H, J=5.3 Hz), 5.43 (s, 1H), 3.10(t, 2H, J=7.5 Hz), 2.79 (m, 1H), 1.79 (m, 2H), 1.45 (m, 2H), 0.92 (t,3H, J=7.5 Hz), 0.81 (m, 2H), 0.58 (m, 2H); MS (ESI) (M+H)⁺ 309.

b)(2E)-1-(2-Butylpyrazolo[1,5-b]pyridazin-3-yl)-3-(dimethylamino)-2-propen-1-one.1-(2-Methylpyrazolo[1,5-b]pyridazin-3-yl)ethanone (165 mg, 0.95 mmol)was added to DMF dimethylacetal (6.0 mL). The reaction was heated at anoil bath temperature of 120° C. for about 3 days. The solvent wasremoved in vacuo. The residue was triturated with diethylether to givethe title compound as a brown solid (60 mg, 26%). The crude material wasused without purification in the next step.

c) 1-(2-Butylpyrazolo[1,5-b]pyridazin-3-yl)ethanone. To a slurry of1-aminopyridazinium iodide (1.60 g, 7.2 mmol) in DMSO (14.0 mL) wasadded 3-hexyne-2-one (1.57 mL, 14.4 mmol). The reaction flask was cooledin an ice bath at 4° C. then KOH (403 mg, 7.2 mmol) and K₂-CO₃ (500 mg,3.6 mmol) were added in one portion. The bath was removed and themixture was stirred at RT for about 1 hour. Water was added (60 mL). Theorganic layer was separated and the aqueous layer was extracted withCH₂Cl₂ (3×50 mL). The combined organic layers were dried (MgSO₄),filtered and concentrated in vacuo. The residue was triturated withdiethyl ether and EtOAc to give the title compound as a red solid (350mg, 26%). ¹H-NMR (300 MHz, CDCl₃) δ 8.65 (dd, 1H, J=9.0, 1.5 Hz), 8.42(dd, 1H, J=4.4, 1.5 Hz), 7.29 (dd, 1H, J=9.0, 4.4 Hz), 3.18 (t, 2H,J=7.5 Hz), 2.65 (s, 3H), 1.88 (m, 2H), 1.54 (m, 2H), 1.02 (t. 3H, J=7.5Hz); MS (APCI) (M+H)⁺ 218.

d) 3-Octyn-2-one. To a solution of hexyne (2.3 mL, 20.0 mmol) in THF(20.0 mL) at −78° C. was added nBuLi (8.0 mL, 20 mmol) in one portion.The reaction mixture was stirred for 10 minutes then dimethylacetamide(1.85 mL, 20 mmol) was added. The cooling bath was removed an themixture was stirred at RT for about 1 hour. Water was added (100 mL)followed by the addition of diethylether (200 mL). The combined organiclayers were dried (MgSO₄), filtered and concentrated in vacuo to givethe title compound as an oil. The crude material was used withoutpurification in the next step.

Example 33N-[4-(4Methyl-1-piperazinyl)phenyl]-4-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) In a similar manner as described in Example 30a, fromN-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl was obtained the titlecompound as a yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.65 (dd, 1H,J=9.0, 1.8 Hz), 8.40 (d, 1H, J=5.2 Hz), 8.29 (dd, 1H, J=4.4, 2.0 Hz),7.47 (d, 2H, J=8.9 Hz), 7.01 (dd, 1H, J=9.1, 4.6 Hz), 6.95 (m, 3H), 3.23(m, 4H), 2.78 (s, 3H), 2.66 (m, 4H), 2.40 (s, 3H); MS (APCI) (M+H)⁺ 401.

Example 344-(2-Ethylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinylphenyl]-2-pyrimidinamine

a) In a similar manner as described in Example 31a, fromN-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl was obtained the titlecompound as a yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.66 (dd, 1H,J=9.1, 1.9 Hz), 8.43 (d, 1H, J=5.2 Hz), 8.31(dd, 1H, J=4.4, 1.9 Hz),7.51 (d, 2H, J=8.9 Hz), 6.9-7.1 (, 5H), 3.25 (m, 4H), 3.16 (q, 2H, J=7.5Hz), 2.65 (m, 4H), 2.42 (s, 3H), 1.49 (t, 3H, J=7.5 Hz); MS (ESI) (M+H)⁺415.

Example 354-(2-Butylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl]phenyl]-2-pyrimidinamine

a) In a similar manner as described in Example 32a, fromN-[4-(4-methyl-1-piperazinyl)phenyl]guanidine.HCl was obtained the titlecompound as a yellow solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.57 (dd, 1H,J=9.0, 1.9 Hz), 8.36 (d, 1H, J=5.3 Hz), 8.24 (dd, 1H, J=4.4, 2.0 Hz),7.43 (d, 2H, J=8.9 Hz), 6.95 (dd, 1H, J=9.0, 4.4 Hz), 6.91 (d, 2H, J=8.9Hz), 6.88 (d, 1H, J=5.2 Hz), 3.17 (m, 4H), 3.09 (t, 2H, J=7.5 Hz), 2.58(m, 4H), 2.34 (s, 3H), 1.82 (m, 2H), 1.44 (m, 2H), 0.93 (t, 3H, J=7.5Hz); MS (ESI) (M+H)⁺ 443.

Example 36N-Cyclopropyl-4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) In a similar manner as described in Example 1a, from(2E)-3-(dimethylamino)-1-(6-methoxypyrazolo[1,5b]pyridazin-3-yl)-2-propen-1-onewas obtained the title compound as a brown solid. ¹H-NMR (300 MHz,CDCl₃) δ 8.95 (d, 1H, J=9.5 Hz), 8.30 (d, 1H, J=5.1 Hz), 8.28 (s, 1H),6.91 (d, 1H, J=5.2 Hz), 6.83 (d, 1H, J=9.4 Hz), 5.39 (s, 1H), 4.09 (s,3H), 2.88 (m, 1H), 0.87 (m, 2H), 0.64 (m, 2H); MS (ESI) (M+H)⁺ 283.

b)(2E)-3-(Dimethylamino)-1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one.In a similar manner as described in Example 30b, from1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)ethanone was obtained thetitle compound as a brown solid. ¹H-NMR (300 MHz, d⁶ DSMO) δ 8.53 (d,1H, J=9.5 Hz), 8.47 (s, 1H), 7.63 (d, 1H, J=12.4 Hz), 7.06 (d, 1H, J=9.5Hz), 5.76 (d, 1H, J=12.4 Hz), 3.96 (s, 3H), 3.10 (bs, 3H), 2.90 (bs,3H); MS (ESI) (M+H)⁺ 247.

c) 1-(6-Methoxypyrazolo[1,5-b]pyridazin-3-yl)ethanone.3-Methoxypyridazine.HCl (16.6 g, 151 mmol) was added to pH 8.0 buffer(250 mL) and heated at 70° C. HOSA (25.6 g, 227 mmol) in water (10 mL)was neutralized to about pH 7.5 by the addition of aqueous KHCO₃ (110mL, 2.4 M). The HOSA solution was added dropwise via addition funnelover one hour. The reaction was cooled to RT and CH₂Cl₂ (250 mL) wasadded. The reaction mixture was cooled in an ice bath and 3-butyne-2-one(5.3 mL, 75 mmol) was added in one portion follwed by the dropwiseaddition of KOH (9.52 g, 169 mmol) in water (25 mL). The reactionmixture was allowed to warm to RT and stirred for about 2 hours. Theaqueous layer was extracted with EtOAc (2×300 mL). The combined organiclayers were washed with water (100 mL), dried. (MgSO₄), and concentratedin vacuo. The residue was triturated with EtOAc and hexanes to give thetitle compound as a red solid (5.6 g, 39%) ¹H-NMR (300 MHz, CDCl₃) δ8.54 (d, 1H, J=9.5 Hz), 8.24 (s, 1H), 6.95 (d, 1H, J=9.5 Hz), 4.09 (s,3H), 2.55 (s, 3H); MS (ESI) (M+H)⁺ 192.

d) 3-Methoxypyridazine.HCl. To a solution of3-chloro-6-methoxypyridazine (2.9 g, 20.0 mmol) in methanol (30 mL) wasadded Pd/C (145 mg, 10% w/w). Hydrogen gas was bubbled through thesolution and then a balloon of hydrogen gas was left over the reactionfor about 12 hours. The reaction was filtered through Celite and thefiltrate collected and concentrated in vacuo. The oil was used withoutfurther purification. ¹H-NMR (300 MHz, CDCl₃) δ 9.47 (d, 1H, J=5.0 Hz),8.26 (dd, 1H, J=9.1, 4.8 Hz), 7.70 (d, 1H, J=8.9 Hz), 4.19 (s, 3H).

Example 374-(6-Methoxypyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine

a) To a solution(2E)-3-(dimethylamino)-1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one(40 mg, 0.16 mmol) in DMF (2.0 mL) was addedN-[4-((methyl-1-piperazinyl)phenyl]guanidine.HCl (99 mg, 0.32 mmol) andpotassium carbonate (112 mg, 0.80 mmol). The reaction was heated at anoil bath temperature of 130° C. for about 18 hours. The mixture wascooled to RT and the solvent was removed in vacuo. The residue wasdissolved in chloroform and filtered. The filtrate was concentrated invacuo then disolved in CH₂Cl₂ and triturated, with diethylether to givethe title compound as a yellow solid (12 mg, 18%). ¹H-NMR (400 MHz,CDCl₃) δ 8.67 (d, 1H, J=9.5 Hz), 8.35 (d, 1H, J=5.2 Hz), 8.29 (s, 1H),7.46 (d, 2H, J=8.9 Hz), 6.98 (m, 3H), 6.90 (s, 1H), 6.75 (d, 1H, J=9.5Hz), 4.09 (s, 3H), 3.23 (m, 4H), 2.64 (m, 4H), 2.39 (s, 3H); MS (ESI)(M+H)⁺ 417.

Example 383-[2-(Cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-ol

a) A solution ofN-cyclopropyl-4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine(510 mg, 1.81 mmol) in morpholine (15 mL) was heated at an oil bathtemperature of 130° C. for about 16 hours. The reaction mixture wascooled and the solvent removed in vacuo. The residue was disolved inCH₂Cl₂ and triturated with diethylether to give the title compound as ayellow solid (400 mg, 82%). ¹H-NMR (300 MHz, d⁶-DMSO) δ 8.96 (d, 1H,J=9.7 Hz), 8.49 (s, 1H), 8.23 (d, 1H, J=5.0 Hz), 7.35 (s, 1H), 7.06 (d,1H, J=5.1 Hz), 6.97 (d, 1H, J=9.5 Hz), 2.74 (m, 1H), 0.73 (m, 2H), 0.49(bs, 2H); MS (ESI) (M+H)⁺ 269.

Example 39N-Cyclopropyl-4-(6-isopropoxyppyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) In a similar manner as described in Example 1a, from(2E)-3-(dimethylamino)-1-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-onewas obtained the title compound as a brown solid. ¹H-NMR (300 MHz,CDCl₃) δ 8.91 (d, 1H, J=9.5 Hz), 8.29 (d, 1H, J=5.2 Hz), 8.25 (s, 1H),6.90 (d, 1H, J=5.3 Hz), 6.76 (d, 1H, J=9.7 Hz), 5.41 (septet, 1H, J=6.2Hz), 5.35 (bs, 1H), 2.85 (m, 1H), 1.43 (d, 6H, J=6.2 Hz), 0.87 (m, 2H),0.63 (m, 2H); MS (ESI) (M+H)⁺ 311.

b)(2E)-3-(Dimethylamino)-1-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-one.In a similar manner as described in Example 30b, from1-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)ethanone (150 mg, 0.7 mmol)was obtained the title compound as a brown solid. This material was usedin the next step without further purification. MS (ESI) (M+H)⁺ 275.

c) 1-(6-Isopropoxypyrazolo[1.5-b]pyridazin-3-yl)ethanone. To a solutionof 1-(6-hydroxypyrazolo[1,5-b]pyridazin-3-yl)ethanone (200 mg, 1.13mmol) in THF (8.0 mL) was added PPh₃ (445 mg, 1.70 mmol), DEAD (296 mg,1.70 mmol) and iPrOH (0.432 mL, 5.65 mmol). The mixture was stirred atRT for about 14 hours. Water (20 mL) was added and the aqueous layer waswashed with EtOAc (3×40 mL). The combined organic layers were dried(MgSO₄) and concentrated in vacuo to give the title compound as a whitesolid. This material was used in the next step without furtherpurification. MS (ESI) (M+H)⁺ 220.

d) 1-(6-Hydroxypyrazolo[1,5-b]pyridazin-3-yl)ethanone. To1-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)ethanone (600 mg, 3.14 mmol)was added HI (10.0 mL, 57% in water). The reaction mixture was heated atan oil bath temperature of 90° C. for about 12 hours. The mixture wascooled to RT, the water layer was brought to pH 8.0 and washed withEtOAc (3×100 mL). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo to give the title compound as a yellow amorphoussolid (365 mg, 63%). ¹H-NMR (300 MHz, dr DMSO) δ 12.25 (bs, 1H),8.48 (s,1H), 8.43 (d, 1H, J=9.5 Hz), 7.07 (d, 1H, J=9.5 Hz), 2.47 (s, 3H); MS(ESI) (M+H)⁺ 178.

Example 40N-[4-(6-Isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinyl]-N-[4-(methyl-1-piperazinyl)phenyl]amine

a) In a similar manner as described in Example 37a, from(2E)-3-(dimethylamino)-1-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-propen-1-onewas obtained the title compound as a brown solid. ¹H-NMR (300 MHz,CDCl₃) δ 8.64 (d, 1H. J=9.6 Hz), 8.34 (d, 1H, J=5.2 Hz), 8.26 (s, 1H),7.46 (d, 2H, J=8.8 Hz), 6.97 (m, 3H), 6.87 (s, 1H), 6.67 (d, 1H, J=9.6Hz), 5.41 (m, 1H), 3.23 (m, 4H), 2.64 (m, 4H), 2.40 (s, 3H), 1.43 (d,6H, J=6.1 Hz); MS (ESI) (M+H)⁺ 445.

Example 413-[2-(Cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate

a) To a solution of3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1.5-b]pyridazin-6-ol(10.0 g, 37.3 mmol) in DMF. (100 mL) was addedN-phenyltrifluoromethylsulfonimide (15.0 g, 42.0 mmol) and DIEA (13 mL,80 mmol). The reaction mixture was stirred at RT for about 2 hours.Water (500 mL) was added and the aqueous layer was washed with EtOAc(3×1 L). The combined organic layers were dried (MgSO₄) and concentratedin vacuo to give the a yellow amorphous solid. The solid was dissolvedin CH₂Cl₂ and purified by slica-gel column, chromatography (gradient,0-10% MeOH in CH₂Cl₂) to give the title compound as a white solid (7.4g, 50%). ¹H-NMR (300 MHz, CDCl₃) δ 9.36 (d, 1H, J=9.5 Hz), 8.54 (s, 1H),8.35 (bs, 1H). 7.17 (d, 1H, J=9.4 Hz), 6.98 (d, 1H, J=5.3 Hz), 5.65 (bs,1H), 2.85 (m, 1H), 0.90 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)⁺ 401.

Example 424-[6-(2-Chlorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-cyclopropyl-2-pyrimidinamine

a) To a solution of3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate (21.0 mg, 0.08 mmol) in DMF (1 mL) was addedPd(PPh₃)₂Cl₂ (5 mg, 0.007 mmol), 2-chlorophenyl boronic acid (15 mg,0.096 mmol), and Na₂-CO₃ (21.0 mg in 0.5 mL water). The reaction mixturewas heated at an oil bath temperature of 100° C. for about 12 hours. Themixture was cooled to RT and water (20 mL) was added. The aqueous layerwas washed with EtOAc (3×50 mL). The combined organic layers were dried(MgSO₄) and concentrated in vacuo and purified by silica-gel columnchromatography (30% EtOAc/hexanes) to give the title compound as a brownsolid (15 mg, 55%). ¹H-NMR (300 MHz, CDCl₃) δ 9.14 (d, 1H, J=9.2 Hz),8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.74-7.71 (m, 1H), 7.56-7.52 (m,2H), 7.46-7.42 (m, 2H), 5.61 (bs, 1H), 2.88 (m, 1H), 0.89 (m, 2H), 0.66(m, 2H); MS (ESI) (M+H)⁺ 363.

Example 43N-Cyclopropyl-4-[6-(2-thienyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) In a similar manner as described in Example 42a, fromthiophene-2-boronic acid was obtained the title compound as a brownsolid. ¹H-NMR (300 MHz, CDCl₃) δ 9.09 (d, 1H, J=9.3 Hz), 8.48 (s, 1H),8.20 (d, 1H, J=5.5 Hz), 7.76 (d, 1H, J=3.3 Hz), 7.63 (d, 1H, J=9.5 Hz),7.54 (d. 1H, J=4.9 Hz), 7.19 (t, 1H, J=4.4 Hz), 6.99 (d, 1H, J=5.8 Hz),2.91 (m, 1H), 0.95 (m, 2H), 0.74 (m, 2H); MS (ESI) (M+H)⁺ 335.

Example 44N-Cyclopropyl-4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) In a similar manner as described in Example 42a, from 4-fluorophenylboronic acid was obtained the title compound as a brown solid. ¹H-NMR(300 MHz, CDCl₃) δ 9.16 (d, 1H, J=9.3 Hz), 8.48 (s, 1H), 8.33 (d, 1H,J=4.6 Hz), 8.09 (dd, 2H, J=8.8, 5.2 Hz), 7.60 (d, 1H, J=9.3 Hz), 7.22(t, 2H, J=8.6 Hz), 6.96 (d, 1H, J=5.2 Hz), 5.47 (bs, 1H), 2.88 (m, 1H),0.90 (m, 2H), 0.67 (m, 2H); MS (APCI) (M+H)⁺ 347.

Example 45N-Cyclopropyl-4-(6-vinylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine

a) To a solution of3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate (100 mg, 0.25 mmol) in DMF (3 mL) was addedPd₂(dba)₃ (12 mg, 0.0125 mmol), LiCl (32 mg, 0.75 mmol), AsPh₃ (31 mg,0.10 mmol), and vinyl-tributylstannane (120 mg, 0.375 mmol). Thereaction mixture was heated at an oil bath temperature of 60° C. forabout 4 hours. The mixture was cooled to RT and water (20 mL) was added.The aqueous layer was washed with EtOAc (3×50 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo and purified bysilica-gel column chromatography (gradient, 10-80% EtOAc in hexanes) togive the title compound as an off-white solid (26 mg, 37%). ¹H-NMR (300MHz, CDCl₃). δ 9.05 (d, 1H, J=9.3 Hz), 8.44 (s, 1H), 8.30 (d, 1H, J=5.3Hz), 7.40 (d, 1H, J=9.4 Hz), 6.92 (m, 2H), 6.22 (d, 1H, J=17.7 Hz), 5.75(d, 1H, J=11.2 Hz), 5.48 (bs, 1H), 2.86 (m, 1H), 0.90 (m, 2H), 0.66 (m,2H); MS (ESI) (M+H)⁺ 279.

Example 46N-Cyclopropyl-4-[6-(4-morphoinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) This product is isolated by silica-gel column chromatography fromExample 41a. ¹H-NMR (300 MHz, d⁶-DMSO) δ 8.88 (d, 1H, J=9.8 Hz), 8.47(s, 1H), 8.22 (d, 1H, J=5.0 Hz), 7.37 (m, 2H), 7.04 (d, 1H, J=5.2 Hz),3.73 (t, 4H, J=4.6 Hz), 3.49 (t, 4H, J=4.7 Hz), 2.74 (m, 1H), 0.73 (m,2H), 0.50 (m, 2H); MS (ESI) (M+H)⁺ 338.

Example 47N-Cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-amine

a) To a solution of3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate (107 mg, 0.268 mmol) in DMF (2 mL) was addedDIEA (0.093 mL, 0.536 mmol) and cyclopentylamine (0.026 mL, 0.268 mmol).The reaction mixture was heated at an oil bath temperature of 50° C. forabout 1 hour at which point N-phenyltrifluoromethylsulfonimide (95 mg,0.268 mmol) was added followed by an additional portion (equivalent) ofcyclopentylamine and DIEA This was repeated two more times. The mixturewas cooled to RT and water (20 mL) was added. The aqueous layer waswashed with EtOAc (3×50 mL). The combined organic layers were dried(MgSO₄) and concentrated in vacuo and purified by silica-gel column 0.15chromatography (gradient, 0-10% MeOH in CH₂Cl₂). The residue wassuspended in EtOAc and triturated with hexanes to give the titlecompound as a yellow solid (26 mg, 29%). ¹H-NMR (300 MHz, CDCl₃) 8.71(d, 1H, J=9.5 Hz), 8.17 (s, 2H), 6.89 (d, 1H, J=5.7 Hz), 6.55 (d, 1H,J=9.3 Hz), 5.92 (bs, 1H), 4.43 (m, 1H), 4.30 (m, 1H), 2.84 (m, 1H), 2.16(m, 2H), 1.71 (m, 4H), 1.50 (m, 2H), 0.87 (m, 2H), 0.66 (m, 2H); MS(APCI) (M+H)⁺ 336.

Example 48N-Cyclopropyl-4-[6-(1-pyrrolidinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) In a similar manner as described in Example 47a, from pyrrolidine wasobtained the title compound as a yellow solid. ¹H-NMR (300 MHz, CDCl₃) δ8.83 (d, 1H, J=9.5 Hz), 8.29 (d, 1H, J=5.4 Hz), 8.20 (s, 1H), 6.92 (d,1H, J=5.4 Hz), 6.74 (d, 1H, J=9.6 Hz), 5.36 (s, 1H), 3.60 (m, 4H), 2.88(m, 1H), 2.09 (m, 4H), 0.90 (m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)⁺ 322.

Example 49N-Cyclopropyl-4-[6-(2-fluoro-4-pyridinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) In a similar manner as described in Example 42a, from2-fluoropyridyl-4-boronic acid was obtained the title compound as abrown solid. ¹H-NMR (400 MHz, CDCl₃) δ 9.29 (bs, 1H), 8.56 (s, 1H), 8.42(d, 1H, J=5.3 Hz), 8.37 (dd, 1H, J=9.5, 5.0 Hz), 7.90 (d, 1H, J=5.1 Hz),7.63 (m, 2H), 6.98 (d, 1H, J=5.1 Hz), 5.41 (s, 1H), 2.88 (m, 1H), 0.91(m, 2H), 0.67 (m, 2H); MS (ESI) (M+H)⁺ 348.

Example 50N-Cyclopropyl-4-[6-(phenylsulfanyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine

a) To a solution of3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate (250 mg, 0.625 mmol) in DMSO (8 mL) was addedPd(PPh₃)₄ (29 mg, 0.025 mmol), benzene thiol (0.064 mL, 0.625 mmol), andNaO^(t)Bu (120 mg, 1.31 mmol). The reaction mixture was heated at an oilbath temperature of 100° C. for about 2 hours. The mixture was cooled toRT and water (40 mL) was added. The aqueous layer was washed with EtOAc(3×60 mL). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo and purified by silica-gel column chromatography(gradient 50-100% EtOAc in hexanes) to give the title compound as ayellow solid (80 mg, 36%). ¹H-NMR (400 MHz, CDCl₃) δ 8.90 (d, 1H, J=9.1Hz), 8.34 (s, 1H), 8.29 (bs, 1H), 7.67 (m, 2H), 7.47 (m, 3H), 6.92 (d,1H, J=5.3 Hz), 6.88 (d, 1H, J=9.4 Hz), 5.38 (s, 1H), 2.82 (m, 1H), 0.85(m, 2H), 0.61 (m, 2H); MS (ESI) (M+H)⁺ 361.

Example 514-[6-(4-Fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-(4-methoxyphenyl)-2-pyrimidinamine

a) To a solution of6-(4-fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine(42 mg, 0.124 mmol) in MeOH (2 mL) was added Oxone (77 mg, 0.124 mmol)in water (1 mL). The reaction mixture was stirred for about 2 hours thenwater (10 mL) was added. The aqueous layer was washed with EtOAc (3×40mL) and aqueous NaHCO₃ (1×20 mL). The combined organic layers were dried(MgSO₄) and concentrated in vacuo to give a brown solid. This solidwas-added to iPrOH (1.0 mL) and 4-methoxyaniline (20 mg, 0.162 mmol) ina sealed tube. The reaction mixture was heated at an oil bathtemperature of 130° C. for about 16 hours. The mixture was cooled to RTand the solid collected by filtration to give the title compound as abrown solid (17 mg, 339% b). ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.41 (s, 1H),9.14 (d, 1H, J=9.1 Hz), 8.88 (s, 1H), 8.41 (d, 1H, J=5.1 Hz), 8.22 (dd,2H, J=8.5, 5.6 Hz), 8.02 (d, 1H, J=9.3 Hz), 7.62 (d, 2H, J=8.8 Hz), 7.42(t, 2H, J=8.8 Hz), 7.30 (d, 1H, J=5.2 Hz), 6.94 (d, 2H, J=8.8 Hz), 3.75(s, 3H); MS (ESI) (M+H)⁺ 413.

b)6-(4-Fluorophenyl)-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1.5-b]pyridazine.In a similar manner as described in Example 44-a, from3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate was obtained the title compound as a brownsolid. ¹H-NMR (300 MHz, CDCl₃) δ 9.02 (d, 1H, J=9.3 Hz), 8.54 (m, 2H),8.10 (m, 2H), 7.69 (d, 1H, J=9.4 Hz), 7.31 (d, 1H, J=5.4 Hz), 7.21 (m,2H), 2.71 (s, 3H); MS (ESI) (M+H)⁺ 338.

c) 3-[2-(Methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate. In a similar manner as described in Example41a, from 3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazin-6-olwas obtained the title compound as a brown solid. ¹H-NMR (300 MHz, DMSOd⁶) δ 8.62 (d, 1H, J=9.9 Hz), 8.62 (s, 1H), 8.52 (d, 1H, J=5.4 Hz), 7.60(d, 1H, J=5.4 Hz), 7.46 (d, 1H, J=9.9 Hz), 2.58 (s, 3H); MS (ESI) (M+H)⁺392.

d) 3-[2-(Methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazin-6-ol. In asimilar manner as described in Example 38a, from6-methoxy-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine wasobtained the title compound as a brown solid. ¹H-NMR (300 MHz, DMSO d⁶)δ 8.57 (d, 1H, J=9.6 Hz), 8.53 (s, 1H), 8.49 (d, 1H, J=5.5 Hz), 7.57 (d,1H, J=5.5 Hz), 6.91 (d, 1H, J=9.6 Hz), 2.57 (s, 3H); MS (ESI) (M+H)⁺260.

e) 6-Methoxy-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazine.In a similar manner as described in Example 36c, from4-ethynyl-2-(methylthio)pyrimidine was obtained the title compound as abrown solid. ¹H-NMR (300 MHz, CDCl₃) δ 8.79 (d, 1H, J=9.6 Hz), 8.45 (d,1H, J=5.3 Hz), 8.30 (s, 1H), 7.21 (d, 1H, J=5.4 Hz), 6.88 (d, 1H, J=9.4Hz), 4.08 (s, 3H), 2.63 (s, 3H); MS (APCI) (M+H)⁺ 274.

f) 4-Ethynyl-2-(methylthio)pyrimidine. To a solution of4-iodo-2-(methylthio)pyrimidine (9.0 g, 35.7 mmol) in DMF (150 mL) wasadded TMS-acetylene (7.0 g, 71;43 mmol), TEA (15 mL, 107 mmol), Cul(0.70 g, 3.57 mmol), and Pd(PPh₃)₂Cl₂ (1.25 g, 1.79 mmol). The reactionmixture was heated at an oil bath temperature of 50° C. for about 1hour. The mixture was cooled to RT and water (40 mL) was added. Theaqueous layer was washed with EtOAc (3×60 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo and purified bysilica-gel column chromatography (gradient 10-40% EtOAc in hexanes) togive a yellow oil. The oil was dissolved in MeOH (20 mL) and cooled to4° C. followed by addition of KF (2.0 g, 35 mmol). The mixture wasstirred for about 5 minutes and poured onto a pad of silica-gel. The padwas washed with 50% EtOAc in hexanes. The fractions containing productwere concentrated in vacuo to give the title compound as a yellow solid(4.0 g, 75%). ¹H-NMR (300 MHz, CDCl₃) δ 8.51 (d, 1H, J=5.0 Hz), 7.07 (d,1H, J=5.0 Hz), 3.34 (s, 1H), 2.57 (s, 3H); MS (ESI) (M+H)⁺ 151.

g) 4-Iodo-2-(methylthio)pyrimidine. 4-Chloro-2-(methylthio)pyrimidine(24.5 g, 153 mmol) was added slowly to HI (100 mL, 30% in H₂O). Thereaction was stirred at RT for about 14 hours. The mixture wasneutralized with aqueous NaHCO₃. The solid was collected by filtrationand dried under vacuum to give the title compound as a white solid (35g, 91%).

Example 524-[6-(4-Fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine

a) In a similar manner as described in Example 51a, from4-(4-methylpiperazin-1-yl)aniline was obtained the title compound as abrown solid. ¹H-NMR (400 MHz, CDCl₃) δ 8.88 (d, 1H, J=9.3 Hz), 8.48 (s,1H), 8.38 (d, 1H, J=5.1 Hz), 8.07 (dd, 2H, J=8.8, 5.3 Hz), 7.50 (t, 3H,J=8.4 Hz), 7.22 (t, 2H, J=8.7 Hz), 7.02-6.98 (m, 3H), 6.94 (s, 1H), 3.23(t, 4H, J=4.9 Hz), 2.63 (m, 4H), 2.38 (s, 3H); MS (ESI) (M+H)⁺ 481.

Example 53N-¹-N¹-Dimethly-N⁴-{4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}-1,4-benzenediamine

a) To a solution3-[2-(methylthio)pyrimidin-4-yl]-6-morpholin-4-ylpyrazolo[1,5-b]pyridazine(116 mg, 0.354 mmol) in MeOH (10 mL) was added Oxone (456 mg, 0.741mmol) in water (4 mL). The reaction mixture was stirred for about 2hours then water (20 mL) was added. The aqueous layer was washed withEtOAc (3×80 mL) and aqueous NaHCO₃ (1×30 mL). The combined organiclayers were dried (MgSO₄) and concentrated in vacuo to give a brownsolid. This solid was added to iPrOH (2.0 mL) andN,N-dimethylbenzene-1,4-diamine (72 mg, 0.53 mmol) in a sealed tube. Thereaction mixture was heated at an oil bath temperature of 130° C. forabout 16 hours. The mixture was cooled to RT and the solid collected byfiltration to give the title compound as a brown solid (18.6 mg, 13%).¹H-NMR (300 MHz, CDCl₃) δ 8.65 (d, 1H, J=9.8 Hz), 8.35 (d, 1H, J=5.4Hz), 8.27 (s, 1H), 7.46 (d, 2H, J=8.9 Hz), 6.97 (d, 1H, J=5.2 Hz),6.88-6.82 (m, 4H), 3.90 (t, 4H, J=4.8 Hz), 3.61 (t, 4H, J=4.9 Hz), 3.01(s, 6H); MS (ESI) (M+H)⁺ 417.

b)3-[2-(Methylthio)pyrimidin-4-yl]-6-morpholin-4-ylpyrazolo[1,5-b]pyridazine.To a solution of3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate (165 mg, 0.635 mmol) in DMF (2 mL) was addedmorpholine (60 mg, 0.697 mmol). The reaction was stirred for about 12hours then water (40 mL) was added. The aqueous layer was washed withEtOAc (3×60 mL). The combined organic layers were dried (MgSO₄) andconcentrated in vacuo and purified by trituration with EtOAc/hexanes togive the title compound as a white solid (85 mg, 41%).

Example 541-(Dimethylamino)-3-[4-({4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}amino)phenoxy]-2-propanol

a) In a similar manner as described in Example 53a, from1-(4-aminophenoxy)-3-(dimethylamino)propan-2-ol was obtained the titlecompound as a brown solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 9.31 (s, 1H),8.78 (bd, 1H, J=9.1 Hz), 8.52 (s, 1H), 8.34 (d, 1H, J=5.3 Hz), 7.58 (d,2H, J=9.0 Hz), 7.35 (d, 1H, J=9.9 Hz), 7.19 (d, 1H, J=5.3 Hz), 6.91 (d,2H, J=9.0 Hz), 4.81, (d, 1H, J=4.4 Hz), 3.94-3.80 (m, 3H), 3.74 (t, 4H,J=4.8 Hz), 3.50 (t, 4H, J=4.7 Hz), 2.38 (dd, 1H, J=12.3, 5.6 Hz), 2.27(dd, 1H, J=12.4, 6.5 Hz); MS (ESI) (M+H)⁺ 491.

Example 55N-(1,3-benzodioxol-5-yl)pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

In a similar manner as described in Example 51, from1,3-benzodioxolan-6-amine was obtained the title compound. ¹H-NMR (300MHz, d⁶-DMSO) δ 9.47 (s, 1H), 9.17 (d, 1H, J=9.1 Hz), 8.90 (s, 1H), 8.64(d, 1H, J=1.8 Hz), 8.46 (d, 1H, J=5.3 Hz), 7.46 (m, 2H), 7.36 (d 1H,J=5.2 Hz), 7.15 (d, 1H, J=8.6 Hz), 6.93 (d, 1H, J=8.4 Hz), 6.02 (s, 2H);MS (ESI) (M+H)⁺ 333.

Example 56N-(2,3-Dihydro-1,4-benzodioxin-6-yl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

In a similar manner as described in Example 51, from1,4-benzodioxan-6-amine was obtained the title compound. ¹H-NMR (300MHz, d⁶-DMSO) δ 9.52 (s, 1H), 9.20 (d, 1H, J=9.6 Hz), 8.92 (s, 1H), 8.64(s 1H), 8.49 (d, 1H, J=5.1 Hz), 7.57 (s, 1H), 7.51 (m, 1H), 7.39 (d, 1H,J=5.2 Hz), 7.27 (d, 1H, J=8.2 Hz), 6.99 (d, 1H, 8.7 Hz), 4.17 (m, 2H),2.12 (m, 2H); MS (ESI) (M+H)⁺ 347.

Example 57N-[3-Methoxy-5-(trifluoromethylphenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(3-methoxy-(5-trifluoromethyl)phenyl)guanidine nitrate was obtainedthe title compound. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.89 (s, 1H), 9.14 (d,1H, J=8.8 Hz), 8.90 (s, 1H), 8.62 (s 1H), 8.53 (d, 1H, J=5.2 Hz), 7.82(s, 1H), 7.65 (s, 1H), 7.45 (m, 2H), 6.83 (s, 1H), 3.31 (s, 3H) MS (ESI)(M+H)⁺ 388.

b) N-(3-Methoxy-(5-trifluoromethyl)phenyl)guanidine nitrate.

In a similar manner as described in Example 7b, from3-methoxy-(5-trifluoromethyl)phenylguanidine nitrate was obtained thetitle compound. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.75 (s, 1H), 7.54 (br s,3H), 7.49-7.09 (m, 3H), 3.83 (s, 3H); MS (ESI) (M+H)⁺ 234.

Example 584-[(4-Pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile

a) In a similar manner as described in Example 1a, fromN-(4-cyanophenyl)guanidine nitrate was obtained the title compound.¹H-NMR (300 MHz, d⁶-DMSO) δ 10.09 (s, 1H), 9.15 (d, 1H, J=8.6 Hz), 8.91(s, 1H), 8.61 (s 1H), 8.54 (d, 1H, J=4.7 Hz), 7.97 (d, 2H, J=8.1 Hz),7.76 (d, 2H, J=8.2 Hz), 7.48 (s, 2H); MS (ESI) (M+H)⁺ 314.

b) N-(4-Cyanophenyl)guanidine nitrate

In a similar manner as described in Example 7b, from 4-aminobenzonitrilewas obtained the title compound. ¹H-NMR (300 MHz, d⁶-DMSO) δ 10.0 (s,1H), 7.87 (d, 2H, J=9.3 Hz), 7.73 (br s, 3H), (d, 2H, J=8.5 Hz); MS(ESI) (M+H)⁺ 161.

Example 59N-(4-Nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

In a similar manner as described in Example 1a, fromN-(4-nitrophenyl)guanidine nitrate was obtained the title compound.¹H-NMR (300 MHz, d⁶-DMSO) δ 10.32 (s, 1H), 9.17 (d, 1H, J=9.0 Hz), 8.91(s, 1H), 8.62 (d 1H, J=4.0 Hz), 8.57 (d, 1H, J=5.3 Hz), 8.22 (d, 2H,J=8.9 Hz), 8.02 (d, 2H, J=9.0 Hz), 7.52 (m, 2H); MS (ESI) (M+H)⁺ 334.

Example 60N-(3-Methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

In a similar manner as described in Example 51a, from 3-methoxyanilinewas obtained the title compound. ¹H-NMR (300 MHz, d⁶-DMSO) δ 9.56 (s,1H), 9.21 (d, 1H. J=9.1 Hz), 8.89 (s, 1H), 8.62 (m, 1H), 8.49 (d, 1H,J=5.3 Hz), 7.47-7.20 (m, 5H), 3.75 (s, 3H); MS (ESI) (M+H)⁺ 319.

Example 61N-(3,5-Dimethylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a, fromN-(3,5-dimethylphenyl)guanidine nitrate was obtained the title compound.¹H-NMR (300 MHz, d⁶-DMSO) δ 9.47 (s, 1H), 9.18 (d, 1H, J=8.8 Hz), 8.92(s, 1H), 8.62 (m, 1H), 8.50 (d, 1H, J=5.1 Hz), 7.48-7.37 (m, 4H), 6.67(s, 1H), 2.29 (s, 6H); MS (ESI) (M+H)⁺317.

b) N-(3,5-Dimethylphenyl)guanidine nitrate

In a similar manner as described in Example 7b, from 3,5-dimethylanilinewas obtained the title compound.

Example 62N-(4-aminosulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 1a except the reactionwas performed using n-butoxyethanol as solvent and was heated in amicrowave at 180° C. for 20 minutes, fromN-(4-aminosulfonylphenyl)guanidine carbonate was obtained the titlecompound as a light yellow solid. ¹H-NMR (400 MHz, d⁶-DMSO) δ 10.0 (s,1H), 9.20 (d, 1H, J=9.2 Hz), 8.94 (s, 1H), 8.64 (dd, 1H, J=2.0, 4.4 Hz),8.55 (d, 1H, J=5.6 Hz), 7.94 (d, 2H, J=8.8 Hz), 7.78 (d, 1H, J=8.8 Hz),7.53-7.47 (m, 2H) 7.21 (s, 2H); MS (ESI) (M+H)⁺ 368.

b) N-(4-aminosulfonylphenyl)guanidine carbonate: To a solution ofsulfanilamide (0.26 g, 1.5 mmol) in conc. HCl (0.4 mL) was addedcyanamide (0.6 mL of a 50% w/w solution in water) The mixture was heatedat an oil bath temperature of 100° C. for about 20 min. The flask wasallowed to cool to RT. The resulting oil was transferred to a beakercontaining ice-cold sat. NaHCO₃. The solution was allowed to cool in thefreezer overnight. The resulting precipitate was filtered and the solidswere dried under vacuum (1 torr) for about 18 hours to give the titlecompound as a white powder (0.32 g, 77%). ¹H-NMR (400 MHz, d⁶-DMSO) δ7.59 (d, 2H, J=8.5 Hz), 6.88 (d, 2H, J=8.0 Hz); MS (ESI) (M+H)⁺ 215.

Example 63N-(4-methylsulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine

a) In a similar manner as described in Example 62a fromN-(4-methylsulfonylphenyl)guanidine carbonate was obtained the titlecompound as an off-white solid ¹H-NMR (400 MHz, d⁶-DMSO) δ 10.13 (s,1H), 9.21 (d, 1H, J=8.8 Hz), 8.95 (s, 1H), 8.65 (dd, 1H, J=2.0, 4.4 Hz),8.57 (d, 1H, J=5.6 Hz), 8.04 (d, 2H, J=8.8 Hz), 7.87 (d, 1H, J=8.8 Hz),7.54-7.49 (m, 2H) 3.18 (s, 3H); MS (ESI) (M+H)⁺ 366.

b) N-(4-methylsulfonylphenyl)guanidine carbonate: In a similar manner asdescribed in Example 62b, from 4-(methylsulfonyl)aniline was obtainedthe title compound.

Biological Data

The compounds of the present invention have valuable pharmacologicproperties. Different compounds from this class are particularlyeffective at inhibiting CDK2 and/or CDK4 enzymes at concentrations,which range from 0.0001 to 1 μM and additionally show specificityrelative to other kinases. Representative data is shown in Table 2following. Substrate phosphorylation assays were carried out as follows.

CDK4

Cyclin D1 and cyclin-dependent kinase 4 were expressed utilizing abaculovirus expression system. The catalytic activity of CDK4 proteinwas assayed by measuring the phosphorylation of Rb protein. A truncatedRb protein (residues 773-928 of the native retinoblastoma protein, fusedto glutathione S-transferase to facilitate purification) was used as thephosphoryl acceptor. The assay conditions were 100 mM HEPES(N-[2-hydroxyethyl]piperzine-N′-[2-ethanesulfonic acid]), pH 7.5, 0.5 μMGST-Rb protein, 1 μCi/mL [³³P]-ATP (1 nM-20 μM), 5-20 mM MgCl₂, 2.5 mMEDTA, 1 mM dithiothreitol, 0.2 mg/mL bovine serum albumin, 2% (v/v)dimethyl sulfoxide (DMSO), CDK4 enzyme (5-50 nM) in a final volume of 50μL Reactions were incubated for time periods of 10-60 min at 30° C. andterminated by the addition of 50 μL quench (1 mM ATP/100 mM EDTA, pH7.0). Detection of protein phosphorylation was accomplished byscintillation counting following collection of protein in 96 well platescoated with Glutathione or trapping of protein onto phosphocellulosefilters. Counts detected by these methodologies minus the appropriatebackground were assumed to be proportional to the reaction initialrates. IC₅₀ values were determined by measuring enzyme activity in thepresence of different inhibitor concentrations (0.1 nM to 50 μM). IC₅₀swere determined by a least squares fit to the equationCPM=Vmax*(1-([I]/(K+[I])))+nsb, or pIC50s were determined by a fit tothe equation CPM=nsb+(Vmax−nsb)/(1+(x/10^(x)−pIC50)), where nsb are thebackground counts.

CDK2

Cyclin dependent protein kinase 2 assays utilized the peptideBiotin-aminohexyl-ARRPMSPKKKA-NH₂ as phosphoryl group acceptor. CDK2 wasexpressed utilizing a baculovirus expression system and was partiallypurified to comprise 20-80% of total protein, with no detectablecompeting reactions present. Typically, assays were performed byincubating enzyme (0.2-10 nM), with and without inhibitor, peptidesubstrate (1-10 nM), [g-³²P]ATP (1-20 nM), and 10-20 mM Mg²⁺ for periodsof time generally within the range 10-120 minutes Reactions wereterminated with 0.2-2 volumes of either 20% acetic acid or 50-100 mMEDTA buffered to pH 7 (substrate consumption <20%). The buffer employedin enzyme assay was 100 mM HEPES pH 7.5 containing 0.1 mg/mL BSA and 5%DMSO. Inhibitors were diluted in 100% DMSO prior to addition into theassay. Detection of peptide phosphorylation was accomplished byscintillation counting following either collection of peptide ontophosphocellulose filters (for reactions stopped with acetic acid),collection of peptide in wells of 96 well plates coated withStreptavidin (Pierce) (reactions were stopped with EDTA), or addition ofAvidin coated Scintillant impregnated beads (Scintillation ProximityAssays from Amersham, reactions were stopped with EDTA). Counts detectedby any of these methodologies minus the appropriate background (assayswith additional 40 mM EDTA or lacking peptide substrate) were assumed tobe proportional to the reaction initial rates, and IC50s were determinedby a least squares fit to the equationCPM=V_(max)*(1-([I]/(K+[I])))+nsb, or −pIC50s were determined by a fitto the equation CPM=nsb+(V_(max)−nsb)/(1+(x/10^(x)−pIC50)), where nsbare the background counts, filters and washed four times with 75 mMphosphoric acid. Radioactivity was determined by liquid scintillationcounting.

TABLE 2 Example # CDK4 inhibition CDK2 inhibition 1 +++ ++ 5 +++ +++ 7+++ +++ 9 +++ +++ 10 +++ +++ 14 +++ +++ 22 +++ +++ 23 +++ +++ 25 +++ +++36 ++ ++ 42 ++ ++ 53 +++ ++ 62 +++ Scale +++ = <0.1 μM ++ = <1.0 μM + =<10 μMAnimal Model for Chemoprotection

Neonatal rat model of chemotherapy-induced alopecia: Time-pregnantfemale Sprague Dawley rats were purchased from Charles River BreedingLaboratories. Rat pups born on the same day were randomized at birth to15 or 16 pups/mom/cage and were housed with moms during the studyperiod. Each experimental group consisted of either 5 or 8 rats. For theetoposide model of CIA, rat pups received etoposide (VePesid, BristolLaboratories Oncology Products, Princeton, N.J.) 6 mg/kg, ip, at 13 daysof age (23). Compounds (0.05-50 mg/mL) were formulated in 100% DMSO andapplied topically to the scalp 4 hours and 2 hours prior to etoposideinjection. For the cyclophosphamide/doxorubicin model of CIA, pupsreceived cyclophosphamide (Cytoxan, Mead Johnson Oncology Products,Princeton, N.J.) 35 mg/kg, ip, on day 12 and doxorubicin (Adriamycin,PharmaciaEtUpjohn Co., Kalamazoo, Mich.) 2.25 mg/kg, ip, on days 12 and13. Compounds were formulated in 100% DMSO and applied topically to thescalp, 50 μL per application. Pups were treated with two topicalapplications of compounds 10 hours and 4 hours (t=−10, −4 hours) on bothdays 12 and 13 prior to chemotherapy administration. Pups were separatedfrom mom during the topical application dosing period to preventgrooming and removal of compound. Cytotoxic-treated rats experiencedwhole body alopecia by 21 days of age. Inhibitor efficacy data wasanalyzed by comparing the % of drug-treated responders and the % ofvehicle-treated responders. The amount of hair present on rat scalp atday 21 were scored and averaged for each inhibitor treated rat andranked as +, ++ and +++.

Example # Rank 7 +++ 9 ++ 14 + 23 +++ 26 +++ 57 + Wherein: + is slighthair coverage ++ is moderate hair coverage +++ is complete hair coverage

-   Wherein:-   + is slight hair coverage-   ++ is moderate hair coverage-   +++ is complete hair coverage

1. A compound of Formula (I):

or a salt thereof: wherein: D is N or CH R¹ is hydrogen, C₁-C₆ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃ alkoxy, halogen, —CF₃, hydroxy,cyano, —S(O)_(y)C₁-C₃ alkyl, or —NR⁴R⁵; y is 0, 1, or 2; a is 1 or 2; R²is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano, azido,nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″, —OS(O)₂R⁹, —S(O)_(y)R¹⁰, —C(O)R⁷,—C(O)OR⁷, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷,—C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, OC(O)R⁷, or —N(R⁸)C(O)R⁸; R³ is -(Q)_(p)-(Q¹)where Q is O, N(R⁸) or S(O)_(y), p is 0 or 1, y is 0, 1, or 2 and Q¹ isC₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl, aryl substitutedwith —C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵, heteroaryl, aralkyl, or—R⁶NR⁴R⁵; R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇cycloalkyl, —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom towhich they are bound, form a heterocyclyl; R⁶ is alkylene, arylene,heteroarylene, C₃-C₇ cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene,or alkynylene; R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl,—S(O)_(y)R¹⁰, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or—N(R⁸)C(O)R⁸; R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or—S(O)₂R⁹; R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl; R¹⁰ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl,cycloalkyl, heterocyclyl, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵,—N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or—N(R⁸)C(O)R⁸; R′ is C₁-C₃ alkylene; and R″ is —OR⁷, —OC(O)NR⁴R⁵,—OC(O)OR⁷, or —OC(O)R⁷.
 2. A compound of Formula (II):

or a salt thereof: wherein: D is N or CH; R¹ is hydrogen, C₁-C₆ alkyl,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃ alkoxy, —CF₃, halogen, hydroxy,cyano, —S(O)_(y)C₁-C₃ alkyl, or —NR⁴R⁵; y is 0, 1, or 2; a is 1 or 2; R²is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano, azido,nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″, —OS(O)₂R⁹, —S(O)_(y)R¹⁰,—C(O)R⁷—C(O)OR⁷, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵,—OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵—NR⁴R⁵, —OC(O)R⁷, or —N(R⁸)C(O)R⁸; Q¹ is C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl, aryl substituted with—C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵, heteroaryl, aralkyl, or —R⁶NR⁴R⁵;R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,—C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they arebound, form a heterocyclyl; R⁶ is alkylene, arylene, heteroarylene,C₃-C₇ cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl,aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵,—OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R⁸ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl,cycloalkyl, heterocyclyl, or —S(O)₂R⁹; R⁹ is C₁-C₆ alkyl or C₁-C₆haloalkyl; R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,—C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R′ is C₁-C₃ alkylene; and R″ is—OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.
 3. A compound of Formula(III):

or a salt thereof: wherein: R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₃ alkoxy, —CF₃, halogen, hydroxy, cyano,—S(O)_(y)C₁-C₃ alkyl, or —NR⁴R⁵; y is 0, 1, or 2; a is 1 or 2; R² ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,—CF₃, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano,azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″, —OS(O)₂R⁹, —S(O)_(y)R¹⁰,—C(O)R⁷, —C(O)OR⁷, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵,—OC(O)OR⁷, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, —OC(O)R⁷, or —N(R⁸)C(O)R⁸; Q¹ is C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, aryl, aryl substituted with—C(O)N(H)R⁶NR⁴R⁵ or —OC(H)(OH)R⁶NR⁴R⁵, heteroaryl, aralkyl, or —R⁶NR⁴R⁵;R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl,—C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atom to which they arebound, form a heterocyclyl; R⁶ is alkylene, arylene, heteroarylene,C₃-C₇ cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene, or alkynylene;R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl,aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵,—OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R⁸ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl,cycloalkyl, heterocyclyl, or —S(O)₂R⁹; R⁹ is C₁-C₆ alkyl or C₁-C₆haloalkyl; R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,—C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R′ is C₁-C₃ alkylene; and R″ is—OR⁷—OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.
 4. A compound of Formula (IV):

or a salt thereof: wherein: R¹ is hydrogen, C₁-C₆ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₁-C₃ alkoxy, C₁-C₆ haloalkyl, halogen, hydroxy, cyano,—S(O)_(y)C₁-C₃ alkyl, or —NR⁴R⁵; y is 0, 1, or 2; a is 1 or 2; R² ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₁-C₆ haloalkyl,C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl, cyano, azido,nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″, —OS(O)₂R⁹, —S(O)_(y)R¹⁰, —C(O)R⁷,—C(O)OR⁷—C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷,—C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, —OC(O)R⁷, or —N(R⁸)C(O)R⁸; b is 1,2, or 3; R^(x)is independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹,aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵,—S(O)_(y)R¹⁰, —SO₂OH, or b is 2 and the two R^(x) groups together withthe phenyl group to which they are bound form a fused group selectedfrom:

wherein R_(y) and R_(z) are independently selected from hydrogen andhalogen,

wherein R is selected from —CF3, halogen, or hydrogen; R⁴ and R⁵ areindependently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, —C(O)R⁹, or R⁴and R⁵, together with the nitrogen atom to which they are bound, form aheterocyclyl; R⁶ is alkylene, arylene, heteroarylene, C₃-C₇cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene, or alkynylene; R⁷ ishydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl,aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —S(O)_(y)R¹⁰, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵,—OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R⁸ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl,cycloalkyl, heterocyclyl, or —S(O)₂R⁹; R⁹ is C₁-C₆ alkyl or C₁-C₆haloalkyl; R¹⁰ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, —C(O)R⁸,—C(O)OR⁸, —C(O)NR⁴R⁵, —N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸,—C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or —N(R⁸)C(O)R⁸; R¹¹ is C₁-C₆ alkyl; R′ is C₁-C₃alkylene; and R″ is —OR⁷, —OC(O)NR⁴R⁵, —OC(O)OR⁷, or —OC(O)R⁷.
 5. Acompound of Formula (IVa):

or a salt thereof: b is 1, 2, or 3; y is 0, 1, or 2; R^(x) isindependently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹,aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵,—S(O)_(y)R¹⁰, —SO₂OH, or b is 2 and the two R^(x) groups together withthe phenyl group to which they are bound form a fused group selectedfrom:

wherein R_(y) and Rz are independently selected from hydrogen andhalogen,

wherein R is selected from —CF3, halogen, or hydrogen; R⁴ and R⁵ areindependently hydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, —C(O)R⁹, or R⁴and R⁵, together with the nitrogen atom to which they are bound, form aheterocyclyl; R⁶ is alkylene, arylene, heteroarylene, C₃-C₇cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene, or alkynylene; R⁹ isC₁-C₆ alkyl or C₁-C₆ haloalkyl; R¹⁰ is NH₂, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, aryl, heteroaryl, or heterocyclyl; and R¹¹ is C₁-C₆ alkyl.6. A compound of Formula (IVa):

or a salt thereof: b is 1, 2, or 3; y is 0, 1, or 2; R^(x) isindependently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹,aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵,—S(O)_(y)R¹⁰, —SO₂OH; R⁴ and R⁵ are independently hydrogen, C₁-C₃ alkyl,C₃-C₇ cycloalkyl, —C(O)R⁹, or R⁴ and R⁵, together with the nitrogen atomto which they are bound, form a heterocyclyl; R⁶ is alkylene, arylene,heteroarylene, C₃-C₇ cycloalkylene, alkenylene, C₃-C₇ cycloalkenylene,or alkynylene; R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl; R¹⁰ is NH₂, C₁-C₆alkyl, C₁-C₆ hydroxyalkyl, aryl, heteroaryl, or heterocyclyl; and R¹¹ isC₁-C₆ alkyl.
 7. A compound as claimed in claim 1, wherein D is N.
 8. Acompound as claimed in claims 1, wherein R¹ is hydrogen or C₁-C₆ alkyl.9. A compound as claimed in claim 1, wherein R¹ is hydrogen.
 10. Acompound as claimed in claim 1, wherein R¹ is C₁-C₆ alkyl.
 11. Acompound as claimed in claim 1, wherein R² is hydrogen, C₁-C₆ alkenyl,heterocyclyl, aryl, heteroaryl, —OR⁸, S(O)_(y)R⁷, and —NR⁴R⁵.
 12. Acompound as claimed in claim 1, wherein R² is hydrogen, heterocyclyl,aryl, heteroaryl, or —OR⁸.
 13. A compound as claimed in claim 1, whereinR² is hydrogen.
 14. A compound as claimed in claim 1, wherein R² is —OR⁸where R⁸ is hydrogen, methyl and isopropyl.
 15. A compound as claimed inclaim 1, wherein R² is heterocyclyl, aryl, or heteroaryl.
 16. A compoundas claimed in claim 1, wherein Q is N(R⁸), p is 1, and Q¹ is C₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl, or aryl.
 17. A compound asclaimed in claim 1, wherein Q is N(R⁸), p is 1, and Q¹ is C₃-C₇cycloalkyl.
 18. A compound as claimed in claim 1, wherein Q is N(R⁸), pis 1, and Q¹ is cyclopropyl.
 19. A compound as claimed in claim 1,wherein Q is N(R⁸), p is 1, and Q¹ is aryl.
 20. A compound as claimed inclaim 1, wherein Q is N(R⁸), p is 1, and Q¹ is phenyl or phenylsubstituted with at least one of C₁-C₆ alkyl, halo, cyano, carboxy,C₁-C₆ haloalkyl, C₁-C₆ alkoxy, nitro, heteroaryl, or heterocyclyl.
 21. Acompound as claimed in claim 4, wherein b is 1, 2, or 3 and R^(x) ishydrogen, halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, —CN, —C(O)OH,—OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹, aryl, heteroaryl,heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵, —S(O)_(y)R¹⁰, or—SO₃H.
 22. A compound as claimed in claim 4, wherein; b is 1 or 2 andR^(x) is halogen, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, —CN, C₁-C₆ haloalkyl,—NO₂, heterocyclyl, or —NR⁴R⁵.
 23. A compound as claimed in claim 4,wherein b is 1 and R^(x) is —CH₃, —CH₂CH₃, —CF₃, —CN, or —NO₂.
 24. Acompound as claimed in claim 4, wherein b is 2 and the two R^(x) groupstogether with the phenyl group to which they are bound form a fusedgroup selected from:

wherein Ry and Rz are independently selected from hydrogen and halogen,

wherein R is selected from —CF3, halogen, or hydrogen.
 25. A compound asclaimed in claim 6, wherein b is 1, 2, or 3; y is 0, 1, or 2; and R^(x)is independently selected from hydrogen, halogen, C₁-C₆ alkyl, C₁-C₆hydroxyalkyl, —CN, —C(O)OH, —OC(O)R¹¹, C₁-C₆ haloalkyl, —NO₂, —OH, —OR⁹,aryl, heteroaryl, heterocyclyl, —NR⁴R⁵, —R⁶NR⁴R⁵, —C(O)N(H)R⁶NR⁴R⁵,—S(O)_(y)R¹⁰, or —SO₃H.
 26. A compound as claimed in claim 6, wherein bis 1 or 2 and R^(x) is independently selected from hydrogen, halogen,C₁-C₆ alkyl, —CN, —C(O)OH, —C₁-C₆ haloalkyl, —NO₂, —OH, or —OR⁹.
 27. Acompound as claimed in claim 6, wherein b is 1 or 2 and R^(x) isindependently selected from hydrogen, halogen, —CN, —C₁-C₆ haloalkyl, or—NO₂.
 28. A compound as claimed in claim 6, wherein b is 1 and R^(x) isselected from —F, —CH₃, —CN, —CF₃, or —NO₂.
 29. A compound as claimed inclaim 1, selected from the group consisting of:N-cyclopropyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-cyclopropyl-N-methyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;4-pyrazolo[1,5-b]pyridazin-3-yl-N-(2,2,2-trifluoroethyl)-2-pyrimidinamine;N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(4-chlorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(4-fluorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;3-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile;4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzoic acid;4-pyrazolo[1,5-b]pyridazin-3-yl-N-[3-(trifluoromethyl)phenyl]-2-pyrimidinamine;N-(3-nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(2-chlorophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(4-methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;4-pyrazolo[1,5-b]pyridazin-3-yl-N-(3,4,5-trimethoxyphenyl)-2-pyrimidinamine;N-[3-(1,3-oxazol-5-yl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1H-benzimidazol-6-amine;N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-benzoxazol-2-amine;N-(6-chloro-1H-benzimidazol-2-yl)-N-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amine;N-(4-chlorobenzyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N¹,N¹-dimethyl-N³-(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)-1,3-propanediaminemethanesulfonate;N-[3-(4-morpholinyl)propyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[3-(4-methyl-1-piperazinyl)propyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;1-{3-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]propyl}-2-pyrrolidinone;N-[3-chloro-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[3-methyl-4-(4-methyl-1-piperazinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[4-(4-methyl-1-piperazinyl)-3-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[3-chloro-4-(4-morpholinyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-{4-[(diethylamino)methyl]phenyl}-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[2-(diethylamino)ethyl]-4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzamide;N-cyclopropyl-4-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;N-cyclopropyl-4-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;4-(2-butylpyrazolo[1,5-b]pyridazin-3-yl)-N-cyclopropyl-2-pyrimidinamine;N-[4-(4-methyl-1-piperazinyl)phenyl]-4-(2-methylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;4-(2-ethylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;4-(2-butylpyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;N-cyclopropyl-4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;4-(6-methoxypyrazolo[1,5-b]pyridazin-3-yl)-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-ol;N-cyclopropyl-4-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;N-[4-(6-isopropoxypyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinyl]-N-[4-(4-methyl-1-piperazinyl)phenyl]amine;3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-yltrifluoromethanesulfonate;4-[6-(2-chlorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-cyclopropyl-2-pyrimidinamine;N-cyclopropyl-4-[6-(2-thienyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;N-cyclopropyl-4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;N-cyclopropyl-4-(6-vinylpyrazolo[1,5-b]pyridazin-3-yl)-2-pyrimidinamine;N-cyclopropyl-4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;N-cyclopentyl-3-[2-(cyclopropylamino)-4-pyrimidinyl]pyrazolo[1,5-b]pyridazin-6-amine;N-cyclopropyl-4-[6-(1-pyrrolidinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;N-cyclopropyl-4-[6-(2-fluoro-4-pyridinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;N-cyclopropyl-4-[6-(phenylsulfanyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinamine;4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-(4-methoxyphenyl)-2-pyrimidinamine;4-[6-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-3-yl]-N-[4-(4-methyl-1-piperazinyl)phenyl]-2-pyrimidinamine;N¹,N¹-dimethyl-N⁴-{4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}-1,4-benzenediamine;1-(dimethylamino)-3-[4-({4-[6-(4-morpholinyl)pyrazolo[1,5-b]pyridazin-3-yl]-2-pyrimidinyl}amino)phenoxy]-2-propanol;N-(1,3-benzodioxol-5-yl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-[3-methoxy-5-(trifluoromethyl)phenyl]-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;4-[(4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinyl)amino]benzonitrile;N-(4-nitrophenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(3-methoxyphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(3,5-dimethylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;N-(4-aminosulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;andN-(4-methylsulfonylphenyl)-4-pyrazolo[1,5-b]pyridazin-3-yl-2-pyrimidinamine;or a salt thereof.
 30. A pharmaceutical composition, comprising: atherapeutically effective amount of a compound as claimed in claim 1, ora salt thereof and one or more of pharmaceutically acceptable carriers,diluents and excipients.
 31. The pharmaceutical composition of claim 30,further comprising at least one anti-neoplastic agent.
 32. A method oftreating breast cancer in a mammal, including administering to saidmammal a therapeutically effective amount of a compound as claimed inclaim 1, or salt thereof.
 33. A method of treating breast cancer in amammal, including administering to said mammal therapeutically effectiveamounts of (i) a compound as claimed in claim 1, or salt thereof and(ii) at least one additional anti-cancer therapy.
 34. A process forpreparing a compound of formula (Q)

comprising, the step of: (i) reacting in the presence of a base acompound of formula (U)

with a compound of formula (E)

wherein R¹ is hydrogen, C₁-C₆ alkyl, C₁-C₄ alkenyl, C₁-C₄ alkynyl, C₁-C₃alkoxy, halogen, hydroxy, cyano, —S(O)_(y)C₁-C₃ alkyl, —NR⁴R⁵; a is 1 or2; and R² is hydrogen, C₁-C₆ alkyl, C₁-C₆ alkenyl, C₁-C₆ alkynyl, C₁-C₆haloalkyl, C₃-C₇ cycloalkyl, halogen, heterocyclyl, aryl, heteroaryl,cyano, azido, nitro, —OR⁸, —OR⁶R⁸, —R⁶R⁷, —R⁶R″, S(O)_(y)R⁷, —C(O)R⁷,—C(O)OR⁷, —C(O)NR⁴R⁵, —NR′(C═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁷,—C(═NR⁴)NR⁴R⁵—NR⁴R⁵, —OC(O)R⁷, —NR⁸C(O)R⁸; R⁴ and R⁵ are independentlyhydrogen, C₁-C₃ alkyl, C₃-C₇ cycloalkyl, —C(O)R⁹, or R⁴ and R⁵, togetherwith the nitrogen atom to which they are bound, form a heterocyclyl; R⁶is alkylene, arylene, heteroarylene, C₃-C₇ cycloalkylene, alkenylene,C₃-C₇ cycloalkenylene, or alkynylene; R⁷ is hydrogen, C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl,heterocyclyl, —S(O)_(y)R¹⁰, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵, —S(O)₂NR⁴R⁵,—N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or—N(R⁸)C(O)R⁸; R⁸ is hydrogen, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,—NR⁴R⁵, aryl, aralkyl, heteroaryl, cycloalkyl, heterocyclyl, or—S(O)₂R⁹; R⁹ is C₁-C₆ alkyl or C₁-C₆ haloalkyl; R¹⁰ is hydrogen, C₁-C₆alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, —NR⁴R⁵, aryl, aralkyl, heteroaryl,cycloalkyl, heterocyclyl, —C(O)R⁸, —C(O)OR⁸, —C(O)NR⁴R⁵,—N(H)R′C(═NR⁴)NR⁴R⁵, —OC(O)NR⁴R⁵, —OC(O)OR⁸, —C(═NR⁴)NR⁴R⁵, —NR⁴R⁵, or—N(R⁸)C(O)R⁸; R′ is C₁-C₃ alkylene; and R″ is —OR⁷, —OC(O)NR⁴R⁵,—OC(O)OR⁷, or —OC(O)R⁷.
 35. A process as claimed in claim 34, whereinthe base is an amine.
 36. A process as claimed in claim 34, wherein thebase is an alkali metal hydroxide.